Mnk inhibitors and methods related thereto

ABSTRACT

The present invention relates to compounds according to Formula (I): 
     
       
         
         
             
             
         
       
     
     or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , W 1 , W 2 , Y and n are as defined herein. Also described are pharmaceutically acceptable compositions of Formula I compounds as well as methods for utilizing the compounds of Formula I and the pharmaceutically acceptable compositions of Formula I compounds as inhibitors of Mnk as well as therapeutics for the treatment of diseases such as cancer.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/611,966, filed Jun. 2, 2017, which is a continuation of U.S.patent application Ser. No. 15/187,854, filed Jun. 21, 2016, now U.S.Pat. No. 9,669,031, which is a divisional of U.S. patent applicationSer. No. 14/748,990, filed Jun. 24, 2015, now U.S. Pat. No. 9,382,248,which claims the benefit of U.S. provisional application No. 62/017,112,filed Jun. 25, 2014, all of which are herein incorporated by referencein their entirety.

FIELD

The present invention generally relates to compounds having activity asinhibitors of MAP kinase interacting kinase (Mnk), as well as to relatedcompositions and methods containing or utilizing the same. Suchcompounds find utility in any number of therapeutic applications,including the treatment of cancer.

BACKGROUND

Eukaryotic initiation factor 4E (eIF4E) is a general translation factor,but it has the potential to enhance preferentially the translation ofmessenger RNAs (mRNAs) that lead to production of malignancy-associatedproteins. This selectivity may relate to an increased requirement foreIF4E and its binding partners for the translation of mRNAs containingextensive secondary structure in their 5′-untranslated regions(5′-UTRs). These mRNAs include those encoding certain proteins thatcontrol cell cycle progression and tumorigenesis. Under normal cellularconditions the translation of these malignancy-associated mRNAs issuppressed as the availability of active eIF4E is limited; however,their levels can increase when eIF4E is over-expressed orhyperactivated. Elevated levels of eIF4E have been found in many typesof tumors and cancer cell lines including cancers of the colon, breast,bladder, lung, prostate, gastrointestinal tract, head and neck,Hodgkin's lymphomas and neuroblastomas.

Initiation of cap-dependent translation is thought to depend on theassembly of eIF4F, an initiation factor complex including eIF4E, thescaffold protein eIF4G, and the RNA helicase eIF4A. Because eIF4E is theonly one of these proteins that binds directly to the mRNA capstructure, it is the key factor for the assembly of eIF4F at the 5′ cap.The scaffold protein, eIF4G, also recruits the 40S ribosomal subunit tothe mRNA via its interaction with eIF3 and binds eIF4B, a protein thataids the RNA-helicase function of eIF4A, thus facilitating thetranslation of mRNAs that contain structured 5′-UTRs. The availabilityof eIF4E as part of the eIF4F complex is a limiting factor incontrolling the rate of translation, and therefore eIF4E is an importantregulator of mRNA translation.

Regulation of eIF4E activity forms a node of convergence of thePI3K/Akt/mTOR and Ras/Raf/MAPK signaling pathways. The PI3K(phosphoinositide 3-kinase)/PTEN (phosphatase and tensin homologuedeleted on chromosome ten)/Akt/mTOR (mammalian target of rapamycin)pathway is often involved in tumorgenesis and in sensitivity andresistance to cancer therapy. Deregulated signaling through thePI3K/PTEN/Akt/mTOR pathway is often the result of genetic alterations incritical components of this pathway and/or mutations at upstream growthfactor receptors or signaling components. PI3K initiates a cascade ofevents when activated by, for example, extracellular growth factors,mitogens, cytokines and/or receptors, PDK1 activates Akt, which in turnphosphorylates and inactivates the tumor suppressor complex comprisingTSC1 and 2 (tuberous sclerosis complex 1/2), resulting in the activationof mTORC1 (target of rapamycin complex 1) by Rheb-GTP. Activation ofPDK1 and Akt by PI3Ks is negatively regulated by PTEN.

PTEN is a critical tumor suppressor gene and is often mutated orsilenced in human cancers. Its loss results in activation of Akt andincreases downstream mTORC1 signaling. The involvement of mTOR complex1(mTORC1) in neoplastic transformation appears to depend on itsregulatory role toward the eIF4F complex; overexpression of eIF4E canconfer resistance to rapamycin. mTORC1 regulates the eIF4F complexassembly that is critical for the translation of mRNAs associated withcell growth, prevention of apoptosis and transformation. mTORC1 achievesthis by phosphorylation and inactivation of 4E-BPs and the subsequentdissociation of 4E-BPs from eIF4E. This then enables eIF4E to interactwith the scaffold protein eIF4G, permitting assembly of the eIF4Fcomplex for the translation of structured mRNAs. mTORC1 also promotesactivation of the translational activator, S6K, which phosphorylates theribosomal protein S6 and other substrates, including eIF4B. mTORC1signaling is inhibited by rapamycin and its analogues (rapalogs),although these compounds act allosterically, rather than directlyinhibiting mTOR kinase activity.

Given the importance of the PI3K/Akt/mTOR pathway in regulating mRNAtranslation of genes that encode for pro-oncogenic proteins andactivated mTORC1 signaling in a high proportion of cancers, thesekinases have been actively pursued as oncology drug targets. A number ofpharmacological inhibitors have been identified, some of which havereached advanced clinical stages. However, it has recently become clearthat the mTOR pathway participates in a complicated feedback loop thatcan impair activation of Akt. It has been shown that prolonged treatmentof cancer cells or patients with mTOR inhibitors causes elevated PI3Kactivity that leads to phosphorylation of Akt and eIF4E, and promotescancer cell survival. eIF4E, acting downstream of Akt and mTOR,recapitulates Akt's action in tumorigenesis and drug resistance, and Aktsignaling via eIF4E is an important mechanism of oncogenesis and drugresistance in vivo.

In addition to the PI3K/Akt/mTOR pathway, eIF4E is also the target ofthe Ras/Raf/MAP signaling cascade which is activated by growth factorsand for the stress-activated p38 MAP kinase pathway. Erk1/2 and p38 thenphosphorylate MAP kinase-interacting kinase 1 (Mnk1) and MAPkinase-interacting kinase 2 (Mnk2). The Erk pathway is also activated inmany cancers, reflecting, for example, activating mutations in Ras(found in around 20% of tumors) or loss of function of the RasGTPase-activator protein NF 1. Mnk1 and Mnk2 are threonine/serineprotein kinases and specifically phosphorylate serine 209 (Ser209) ofeIF4E within the eIF4F complex, by virtue of the interaction betweeneIF4E and the Mnks, which serves to recruit Mnks to act on eIF4E. Micewith mutated eIF4E, in which Ser209 is replaced by alanine, show noeIF4E phosphorylation and significantly attenuated tumor growth.Significantly, while Mnk activity is necessary for eIF4E-mediatedoncogenic transformation, it is dispensable for normal development.Pharmacologically inhibiting Mnks thus presents an attractivetherapeutic strategy for cancer.

Despite increased understanding of Mnk structure and function, littleprogress has been made with regard to the discovery of pharmacologicalMnk inhibitors and relatively few Mnk inhibitors have been reported:CGP052088 (Tschopp et al., Mol Cell Biol Res Commun. 3(4):205-211,2000); CGP57380 (Rowlett et al., Am J Physiol Gastrointest LiverPhysiol. 294(2):G452-459, 2008); and Cercosporamide (Konicek et al.,Cancer Res. 71(5):1849-1857, 2011). These compounds, however, havemainly been used for the purpose of Mnk target validation. Morerecently, investigators have proposed further compounds for treatingdiseases influenced by the inhibition of kinase activity of Mnk1 and/orMnk2, including, for example, the compounds disclosed in WO 2014/044691and the various patent documents cited therein and the4-(dihydropyridinon-3-yl)amino-5-methylthieno[2,3,-d]pyrimidinesdisclosed by Yu et al., European Journal of Med. Chem., 95: 116-126,2015.

Accordingly, while advances have been made in this field there remains asignificant need in the art for compounds that specifically inhibit Mnkkinase activity, particularly with regard to Mnk's role in regulation ofcancer pathways, as well as for associated composition and methods. Thepresent invention fulfills this need and provides further relatedadvantages.

SUMMARY

The present invention is directed to compounds that inhibit or modulatethe activity of Mnk, as well as stereoisomers, tautomers andpharmaceutically acceptable salts of such compounds as candidatetherapeutic agents. The present invention also is directed tocompositions containing such compounds and associated methods fortreating conditions that would benefit from Mnk inhibition, such ascancer.

In one embodiment, the invention is directed to compounds that conformto Formula I as well as to a stereoisomer, tautomer or pharmaceuticallyacceptable salt of such compounds.

For Formula I compounds, R¹, R², R³, R^(4a), R^(4b), R⁶, R⁷, R⁸, W², Yand “n” are as defined below.

In another embodiment, compositions are disclosed comprising a compoundof structure (I) in combination with a pharmaceutically acceptablecarrier, diluent or excipient.

In a further embodiment, methods are provided for treating a Mnkdependent condition in a mammal in need thereof. Such methods compriseadministering an effective amount of a compound of structure (I), orcompositions comprising the same, to the mammal. Such conditionsinclude, but are not limited to, various forms of cancer as discussed inmore detail below.

These and other aspects of the invention will be apparent upon referenceto the following detailed description. To this end, various referencesare set forth herein which describe in more detail certain backgroundinformation, procedures, compounds and/or compositions, and are eachhereby incorporated by reference in their entirety.

FIGURES

FIG. 1 illustrates XRPD data for the hydrogen chloride salt form of anexemplary Formula I compound.

DETAILED DESCRIPTION

In the following description, certain specific details are set forth inorder to provide a thorough understanding of various embodiments of theinvention. However, one skilled in the art will understand that theinvention may be practiced without these details. Unless the contextrequires otherwise, throughout the present specification and claims, theword “comprise” and variations thereof, such as, “comprises” and“comprising” are to be construed in an open, inclusive sense (i.e., as“including, but not limited to”).

Reference throughout this specification to “one embodiment” or “anembodiment” means that a particular feature, structure or characteristicdescribed in connection with the embodiment is included in at least oneembodiment of the present invention. Thus, the appearances of thephrases “in one embodiment” or “in an embodiment” in various placesthroughout this specification are not necessarily all referring to thesame embodiment. Furthermore, the particular features, structures, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Definitions

As used herein, and unless noted to the contrary, the following termsand phrases have the meaning noted below.

“Amino” refers to the —NH₂ substituent.

“Aminocarbonyl” refers to the —C(O)NH₂ substituent.

“Carboxyl” refers to the —CO₂H substituent.

“Carbonyl” refers to a —C(O)— or —C(═O)— group. Both notations are usedinterchangeably within the specification.

“Cyano” refers to the —C≡N substituent.

“Cyanoalkylene” refers to the -(alkylene)C≡N substituent.

“Acetyl” refers to the —C(O)CH₃ substituent.

“Hydroxy” or “hydroxyl” refers to the —OH substituent.

“Hydroxyalkylene” refers to the -(alkylene)OH substituent.

“Oxo” refers to an oxygen of —O— substituent.

“Thio” or “thiol” refer to a —SH substituent.

The phrase “MAP kinase interacting kinase” or the term “Mnk” refers toall isoforms of the MAP kinase interacting kinase protein includingMnk-1 and Mnk-2.

“Alkyl” refers to a saturated, straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, having from oneto twelve carbon atoms (C₁-C₁₂ alkyl), from one to eight carbon atoms(C₁-C₈ alkyl) or from one to six carbon atoms (C₁-C₆ alkyl), and whichis attached to the rest of the molecule by a single bond. Exemplaryalkyl groups include methyl, ethyl, n-propyl, 1-methylethyl(iso-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl),3-methylhexyl, 2-methylhexyl, and the like.

“Lower alkyl” has the same meaning as alkyl defined above but havingfrom one to four carbon atoms (C₁-C₄ alkyl).

“Alkenyl” refers to an unsaturated alkyl group having at least onedouble bond and from two to twelve carbon atoms (C₂-C₁₂ alkenyl), fromtwo to eight carbon atoms (C₂-C₈ alkenyl) or from two to six carbonatoms (C₂-C₆ alkenyl), and which is attached to the rest of the moleculeby a single bond, e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl,and the like.

“Alkynyl” refers to an unsaturated alkyl group having at least onetriple bond and from two to twelve carbon atoms (C₂-C₁₂ alkynyl), fromtwo to ten carbon atoms (C₂-C₁₀ alkynyl) from two to eight carbon atoms(C₂-C₈ alkynyl) or from two to six carbon atoms (C₂-C₆ alkynyl), andwhich is attached to the rest of the molecule by a single bond, e.g.,ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

“Alkylene” or “alkylene chain” refers to a straight or branched divalenthydrocarbon (alkyl) chain linking the rest of the molecule to a radicalgroup, consisting solely of carbon and hydrogen, respectively. Alkylenescan have from one to twelve carbon atoms, e.g., methylene, ethylene,propylene, n-butylene, and the like. The alkylene chain is attached tothe rest of the molecule through a single or double bond. The points ofattachment of the alkylene chain to the rest of the molecule can bethrough one carbon or any two carbons within the chain. “Optionallysubstituted alkylene” refers to alkylene or substituted alkylene.

“Alkenylene” refers to divalent alkene. Examples of alkenylene includewithout limitation, ethenylene (—CH═CH—) and all stereoisomeric andconformational isomeric forms thereof. “Substituted alkenylene” refersto divalent substituted alkene. “Optionally substituted alkenylene”refers to alkenylene or substituted alkenylene.

“Alkynylene” refers to divalent alkyne. Examples of alkynylene includewithout limitation, ethynylene, propynylene. “Substituted alkynylene”refers to divalent substituted alkyne.

“Alkoxy” refers to a radical of the formula —OR_(a) where R_(a) is analkyl having the indicated number of carbon atoms as defined above.Examples of alkoxy groups include without limitation —O-methyl(methoxy), —O-ethyl (ethoxy), —O-propyl (propoxy), —O— isopropyl (isopropoxy) and the like.

“Acyl” refers to a radical of the formula —C(O)R_(a) where R_(a) is analkyl having the indicated number of carbon atoms.

“Alkylaminyl” refers to a radical of the formula —NHR_(a) or—NR_(a)R_(a) where each R_(a) is, independently, an alkyl radical havingthe indicated number of carbon atoms as defined above.

“Cycloalkylaminyl” refers to a radical of the formula —NHR_(a) whereR_(a) is a cycloalkyl radical as defined herein.

“Alkylcarbonylaminyl” refers to a radical of the formula —NHC(O)R_(a),where R_(a) is an alkyl radical having the indicated number of carbonatoms as defined herein.

“Cycloalkylcarbonylaminyl” refers to a radical of the formula—NHC(O)R_(a), where R_(a) is a cycloalkyl radical as defined herein.

“Alkylaminocarbonyl” refers to a radical of the formula —C(O)NHR_(a) or—C(O)NR_(a)R_(a), where each R_(a) is independently, an alkyl radicalhaving the indicated number of carbon atoms as defined herein.

“Cyclolkylaminocarbonyl” refers to a radical of the formula—C(O)NHR_(a), where R_(a) is a cycloalkyl radical as defined herein.

“Aryl” refers to a hydrocarbon ring system radical comprising hydrogen,6 to 18 carbon atoms and at least one aromatic ring. Exemplary aryls arehydrocarbon ring system radical comprising hydrogen and 6 to 9 carbonatoms and at least one aromatic ring; hydrocarbon ring system radicalcomprising hydrogen and 9 to 12 carbon atoms and at least one aromaticring; hydrocarbon ring system radical comprising hydrogen and 12 to 15carbon atoms and at least one aromatic ring; or hydrocarbon ring systemradical comprising hydrogen and 15 to 18 carbon atoms and at least onearomatic ring. For purposes of this invention, the aryl radical may be amonocyclic, bicyclic, tricyclic or tetracyclic ring system, which mayinclude fused or bridged ring systems. Aryl radicals include, but arenot limited to, aryl radicals derived from aceanthrylene,acenaphthylene, acephenanthrylene, anthracene, azulene, benzene,chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane,indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, andtriphenylene. “Optionally substituted aryl” refers to an aryl group or asubstituted aryl group.

“Arylene” denotes divalent aryl, and “substituted arylene” refers todivalent substituted aryl.

“Aralkyl” or “araalkylene” may be used interchangeably and refer to aradical of the formula —R_(b)—R_(c), where R_(b) is an alkylene chain asdefined herein and R_(c) is one or more aryl radicals as defined herein,for example, benzyl, diphenylmethyl and the like.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which may include fused or bridged ring systems, having from three tofifteen carbon atoms, preferably having from three to ten carbon atoms,three to nine carbon atoms, three to eight carbon atoms, three to sevencarbon atoms, three to six carbon atoms, three to five carbon atoms, aring with four carbon atoms, or a ring with three carbon atoms. Thecycloalkyl ring may be saturated or unsaturated and attached to the restof the molecule by a single bond. Monocyclic radicals include, forexample, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. Polycyclic radicals include, for example, adamantyl,norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

“Cycloalkylalkylene” or “cycloalkylalkyl” may be used interchangeablyand refer to a radical of the formula —R_(b)R_(e) where R_(b) is analkylene chain as defined herein and R_(e) is a cycloalkyl radical asdefined herein. In certain embodiments, R_(b) is further substitutedwith a cycloalkyl group, such that the cycloalkylalkylene comprises twocycloalkyl moieties. Cyclopropylalkylene and cyclobutylalkylene areexemplary cycloalkylalkylene groups, comprising at least one cyclopropylor at least one cyclobutyl group, respectively.

“Fused” refers to any ring structure described herein which is fused toan existing ring structure in the compounds of the invention. When thefused ring is a heterocyclyl ring or a heteroaryl ring, any carbon atomon the existing ring structure which becomes part of the fusedheterocyclyl ring or the fused heteroaryl ring may be replaced with anitrogen atom.

“Halo” or “halogen” refers to bromo (bromine), chloro (chlorine), fluoro(fluorine), or iodo (iodine).

“Haloalkyl” refers to an alkyl radical having the indicated number ofcarbon atoms, as defined herein, wherein one or more hydrogen atoms ofthe alkyl group are substituted with a halogen (halo radicals), asdefined above. The halogen atoms can be the same or different. Exemplaryhaloalkyls are trifluoromethyl, difluoromethyl, trichloromethyl,2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl,1,2-dibromoethyl, and the like.

“Heterocyclyl”, heterocycle”, or “heterocyclic ring” refers to a stable3- to 18-membered saturated or unsaturated radical which consists of twoto twelve carbon atoms and from one to six heteroatoms, for example, oneto five heteroatoms, one to four heteroatoms, one to three heteroatoms,or one to two heteroatoms selected from the group consisting ofnitrogen, oxygen and sulfur. Exemplary heterocycles include withoutlimitation stable 3-15 membered saturated or unsaturated radicals,stable 3-12 membered saturated or unsaturated radicals, stable 3-9membered saturated or unsaturated radicals, stable 8-membered saturatedor unsaturated radicals, stable 7-membered saturated or unsaturatedradicals, stable 6-membered saturated or unsaturated radicals, or stable5-membered saturated or unsaturated radicals.

Unless stated otherwise specifically in the specification, theheterocyclyl radical may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heterocyclylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized; and the heterocyclyl radical may be partially or fullysaturated. Examples of non-aromatic heterocyclyl radicals include, butare not limited to, azetidinyl, dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl,isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl,piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl,quinuclidinyl, thiazolidinyl, tetrahydrofuryl, thietanyl, trithianyl,tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl,1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Heterocyclylsinclude heteroaryls as defined herein, and examples of aromaticheterocyclyls are listed in the definition of heteroaryls below.

“Heterocyclylalkyl” or “heterocyclylalkylene” refers to a radical of theformula —R_(b)R_(f) where R_(b) is an alkylene chain as defined hereinand R_(f) is a heterocyclyl radical as defined above, and if theheterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl maybe attached to the alkyl radical at the nitrogen atom.

“Heteroaryl” or “heteroarylene” refers to a 5- to 14-membered ringsystem radical comprising hydrogen atoms, one to thirteen carbon atoms,one to six heteroatoms selected from the group consisting of nitrogen,oxygen and sulfur, and at least one aromatic ring. For purposes of thisinvention, the heteroaryl radical may be a stable 5-12 membered ring, astable 5-10 membered ring, a stable 5-9 membered ring, a stable 5-8membered ring, a stable 5-7 membered ring, or a stable 6 membered ringthat comprises at least 1 heteroatom, at least 2 heteroatoms, at least 3heteroatoms, at least 4 heteroatoms, at least 5 heteroatoms or at least6 heteroatoms. Heteroaryls may be a monocyclic, bicyclic, tricyclic ortetracyclic ring system, which may include fused or bridged ringsystems; and the nitrogen, carbon or sulfur atoms in the heteroarylradical may be optionally oxidized; the nitrogen atom may be optionallyquaternized. The heteroatom may be a member of an aromatic ornon-aromatic ring, provided at least one ring in the heteroaryl isaromatic. Examples include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl,benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl,benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl,benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl,carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl,furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl,isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl,oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl,1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl,quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl,tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl,triazinyl, and thiophenyl (i.e. thienyl).

“Heteroarylalkyl” or “heteroarylalkylene” refers to a radical of theformula —R_(b)R_(g) where R_(b) is an alkylene chain as defined aboveand R_(g) is a heteroaryl radical as defined above.

“Thioalkyl” refers to a radical of the formula —SR_(a) where R_(a) is analkyl radical as defined above containing one to twelve carbon atoms, atleast 1-10 carbon atoms, at least 1-8 carbon atoms, at least 1-6 carbonatoms, or at least 1-4 carbon atoms.

“Heterocyclylaminyl” refers to a radical of the formula —NHR_(f) whereR_(f) is a heterocyclyl radical as defined above.

“Thione” refers to a ═S group attached to a carbon atom of a saturatedor unsaturated (C₃-C₈)cyclic or a (C₁-C₈)acyclic moiety.

“Sulfoxide” refers to a —S(O)— group in which the sulfur atom iscovalently attached to two carbon atoms.

“Sulfone” refers to a —S(O)₂— group in which a hexavalent sulfur isattached to each of the two oxygen atoms through double bonds and isfurther attached to two carbon atoms through single covalent bonds.

The term “oxime” refers to a —C(R_(a))═N—OR_(a) radical where R_(a) ishydrogen, lower alkyl, an alkylene or arylene group as defined above.

The compound of the invention can exist in various isomeric forms, aswell as in one or more tautomeric forms, including both single tautomersand mixtures of tautomers. The term “isomer” is intended to encompassall isomeric forms of a compound of this invention, including tautomericforms of the compound.

Some compounds described here can have asymmetric centers and thereforeexist in different enantiomeric and diastereomeric forms. A compound ofthe invention can be in the form of an optical isomer or a diastereomer.Accordingly, the invention encompasses compounds of the invention andtheir uses as described herein in the form of their optical isomers,diastereoisomers and mixtures thereof, including a racemic mixture.Optical isomers of the compounds of the invention can be obtained byknown techniques such as asymmetric synthesis, chiral chromatography, orvia chemical separation of stereoisomers through the employment ofoptically active resolving agents.

Unless otherwise indicated, “stereoisomer” means one stereoisomer of acompound that is substantially free of other stereoisomers of thatcompound. Thus, a stereomerically pure compound having one chiral centerwill be substantially free of the opposite enantiomer of the compound. Astereomerically pure compound having two chiral centers will besubstantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, for example greater than about 90%by weight of one stereoisomer of the compound and less than about 10% byweight of the other stereoisomers of the compound, or greater than about95% by weight of one stereoisomer of the compound and less than about 5%by weight of the other stereoisomers of the compound, or greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

If there is a discrepancy between a depicted structure and a name givento that structure, then the depicted structure controls. Additionally,if the stereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it. In some cases, however, where more than one chiralcenter exists, the structures and names may be represented as singleenantiomers to help describe the relative stereochemistry. Those skilledin the art of organic synthesis will know if the compounds are preparedas single enantiomers from the methods used to prepare them.

In this description, a “pharmaceutically acceptable salt” is apharmaceutically acceptable, organic or inorganic acid or base salt of acompound of the invention. Representative pharmaceutically acceptablesalts include, e.g., alkali metal salts, alkali earth salts, ammoniumsalts, water-soluble and water-insoluble salts, such as the acetate,amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate,benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide,butyrate, calcium, calcium edetate, camsylate, carbonate, chloride,citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate,esylate, fiunarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate,N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate,oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate,einbonate), pantothenate, phosphate/diphosphate, picrate,polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate,subacetate, succinate, sulfate, sulfosaliculate, suramate, tannate,tartrate, teoclate, tosylate, triethiodide, and valerate salts. Apharmaceutically acceptable salt can have more than one charged atom inits structure. In this instance the pharmaceutically acceptable salt canhave multiple counterions. Thus, a pharmaceutically acceptable salt canhave one or more charged atoms and/or one or more counterions.

The terms “treat”, “treating” and “treatment” refer to the ameliorationor eradication of a disease or symptoms associated with a disease. Incertain embodiments, such terms refer to minimizing the spread orworsening of the disease resulting from the administration of one ormore prophylactic or therapeutic agents to a patient with such adisease.

The term “effective amount” refers to an amount of a compound of theinvention or other active ingredient sufficient to provide a therapeuticor prophylactic benefit in the treatment or prevention of a disease orto delay or minimize symptoms associated with a disease. Further, atherapeutically effective amount with respect to a compound of theinvention means that amount of therapeutic agent alone, or incombination with other therapies, that provides a therapeutic benefit inthe treatment or prevention of a disease. Used in connection with acompound of the invention, the term can encompass an amount thatimproves overall therapy, reduces or avoids symptoms or causes ofdisease, or enhances the therapeutic efficacy or synergies with anothertherapeutic agent.

The terms “modulate”, “modulation” and the like refer to the ability ofa compound to increase or decrease the function, or activity of, forexample, MAP kinase interacting kinase (Mnk). “Modulation”, in itsvarious forms, is intended to encompass inhibition, antagonism, partialantagonism, activation, agonism and/or partial agonism of the activityassociated with Mnk. Mnk inhibitors are compounds that bind to,partially or totally block stimulation, decrease, prevent, delayactivation, inactivate, desensitize, or down regulate signaltransduction. The ability of a compound to modulate Mnk activity can bedemonstrated in an enzymatic assay or a cell-based assay.

A “patient” or subject” includes an animal, such as a human, cow, horse,sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbitor guinea pig. The animal can be a mammal such as a non-primate and aprimate (e.g., monkey and human). In one embodiment, a patient is ahuman, such as a human infant, child, adolescent or adult.

The term “prodrug” refers to a precursor of a drug that is a compoundwhich upon administration to a patient must undergo chemical conversionby metabolic processes before becoming an active pharmacological agent.Exemplary prodrugs of compounds in accordance with Formula I are esters,acetamides, and amides.

Compounds of the Invention

The present invention is generally directed to compounds encompassed bythe genus of Formula I

or a stereoisomer, tautomer or pharmaceutically acceptable salt thereofwherein:

W¹ and W² are independently O, S or N—OR′, where R′ is lower alkyl;

Y is —N(R⁵)—, —O—, —S—, —C(O)—, —S═O, —S(O)₂—, or —CHR⁹—;

R¹ is hydrogen, lower alkyl, cycloalkyl or heterocyclyl wherein anylower alkyl, cycloalkyl or heterocyclyl is optionally substituted with1, 2 or 3 J groups;

n is 1, 2 or 3;

R² and R³ are each independently hydrogen, alkyl, alkenyl, alkynyl,aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl,cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, wherein anyalkyl, aryl, araalkylene, heteroaryl, heteroarylalkylene, cycloalkyl,cycloalkylalkylene, heterocyclyl, or heterocyclylalkylene, is optionallysubstituted with 1, 2 or 3 J groups;

or R² and R³ taken together with the carbon atom to which they areattached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl orheterocyclyl is optionally substituted with 1, 2 or 3 J groups;

R^(4a) and R^(4b) are each independently hydrogen, halogen, hydroxyl,thiol, hydroxyalkylene, cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heterocyclyl;

R⁵ is hydrogen, cyano, or lower alkyl;

or R⁵ and R⁸ taken together with the atoms to which they are attachedform a fused heterocyclyl optionally substituted with 1, 2 or 3 Jgroups;

R⁶, R⁷ and R⁸ are each independently hydrogen, hydroxy, halogen, cyano,amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene,cycloalkylalkenylene, alkylaminyl, alkylcarbonylaminyl,cycloalkylcarbonylaminyl, cycloalkylaminyl, heterocyclylaminyl,heteroaryl, or heterocyclyl, and wherein any amino, alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene,amino, alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl,cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl isoptionally substituted with 1, 2 or 3 J groups;

or R⁷ and R⁸ taken together with the atoms to which they are attachedform a fused heterocyclyl or heteroaryl optionally substituted with 1, 2or 3 J groups;

J is —SH, —SR⁹, —S(O)R⁹, —S(O)₂R⁹, —S(O)NH₂, —S(O)NR⁹R⁹, —NH₂, —NR⁹R⁹,—COOH, —C(O)OR⁹, —C(O)R⁹, —C(O)—NH₂, —C(O)—NR⁹R⁹, hydroxy, cyano,halogen, acetyl, alkyl, lower alkyl, alkenyl, alkynyl, alkoxy,haloalkyl, thioalkyl, cyanoalkylene, alkylaminyl, NH₂—C(O)-alkylene,NR⁹R⁹—C(O)-alkylene, —CHR⁹—C(O)-lower alkyl, —C(O)-lower alkyl,alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene,cycloalkylalkenylene, cycloalkylcarbonylaminyl, cycloalkylaminyl,—CHR⁹—C(O)-cycloalkyl, —C(O)-cycloalkyl, —CHR⁹—C(O)-aryl, —CHR⁹-aryl,—C(O)-aryl, —CHR⁹—C(O)-heterocycloalkyl, —C(O)-heterocycloalkyl,heterocyclylaminyl, or heterocyclyl; or any two J groups bound to thesame carbon or hetero atom may be taken together to form oxo; and

R⁹ is hydrogen, lower alkyl or —OH.

In one embodiment of structure (I), the present disclosure provides acompound having the following structure (Ia), as well as stereoisomers,tautomers or pharmaceutically acceptable salts thereof.

For Formula Ia compounds, substituent R¹ is hydrogen or lower alkyl andsubscript n is 1, 2 or 3. Substituents R² and R³ in Formula Ia are eachindependently hydrogen, alkyl, cycloalkyl, cycloalkylalkylene,heterocyclyl or heterocyclylalkyl, and any such alkyl, cycloalkyl,cycloalkylalkylene, heterocyclyl or heterocyclylalkyl can optionally besubstituted with 1, 2 or 3 J groups.

Substitutents R² and R³ in Formula Ia when taken together with thecarbon atom to which they are attached can form a cycloalkyl orheterocyclyl, wherein any such cycloalkyl or heterocyclyl is optionallysubstituted with 1, 2 or 3 J groups. In Formula Ia, R^(4a) is hydrogen,halogen, hydroxy, alkyl, alkoxy, thioalkyl, alkenyl or cycloalkyl andsubstituent R⁵ is hydrogen or lower alkyl.

Alternatively, substituent groups R⁵ and R⁸ taken together with theatoms to which they are attached form a fused heterocyclyl that isoptionally substituted with 1, 2 or 3 J groups.

In one embodiment, substituents R⁶, R⁷ and R⁸ are independently and ateach occurrence hydrogen, halogen, alkyl, alkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, amino, alkylaminyl,alklycarbonylaminyl, cycloalkylcarbonylaminyl, alkylaminyl orcycloalkylaminyl, and any such alkyl, alkenyl, cycloalkyl,cycloalkylalkyl, cycloalkylalkenyl, amino, alkylaminyl,alklycarbonylaminyl, cycloalkylcarbonylaminyl, alkylaminyl orcycloalkylaminyl is optionally substituted with 1, 2 or 3 J groups. Forsome compounds in accordance with Formula Ia, R⁷ and R⁸ taken togetherwith the atoms to which they are attached form a fused heterocyclylunsubstituted or substituted with 1, 2 or 3 J groups.

Variable J in Formula Ia is —SH, —SR⁹, —S(O) R⁹, —S(O)₂ R⁹, —S(O)NH₂,—S(O)NR⁹R⁹, —NH₂, —NR⁹R⁹, —COOH, —C(O)OR⁹, —C(O)R⁹, —C(O)— NH₂,—C(O)—NR⁹R⁹, hydroxy, cyano, halogen, acetyl, alkyl, lower alkyl,alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene,alkylaminyl, NH₂—C(O)-alkylene, NR⁹R⁹—C(O)-alkylene, —CHR⁹—C(O)-loweralkyl, —C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl,cycloalkylalkylene, cycloalkylalkenylene, cycloalkyl carbonylaminyl,cycloalkylaminyl, —CHR⁹—C(O)-cycloalkyl, —C(O)-cycloalkyl,—CHR⁹—C(O)-aryl, —CHR⁹-aryl, —C(O)-aryl, —CHR⁹—C(O)-heterocycloalkyl,—C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl. For some ofthe inventive compounds according to Formula Ia, any two J groups boundto the same carbon or hetero atom may be taken together to form an oxogroup.

In some embodiments, variable J in Formula Ia is halogen, amino, alkyl,haloalkyl, alkylaminyl, cycloalkyl or heterocyclyl. Alternatively, forcertain Formula Ia compounds, any two J groups when bound to the samecarbon or hetero atom may be taken together to form oxo group.

The present invention is further directed to compounds according toFormula IIa, illustrated below, where variable Y is —N(R⁵)— andsubscript “n” is 1.

According to one embodiment, variable Y in Formula I is —O—, —S—,—C(O)—, sulfoxide, sulfone, —CHR⁹— or —CH₂—, subscript “n” is 1 and theinventive compounds conform to Formula IIb. When “Y” is —CHR⁹— inFormula IIb, substituent R⁹ is hydrogen, lower alkyl or hydroxy.

In another embodiment of the invention, variable “Y” in Formula I is—N(R⁵)—, subscript “n” is 2 or 3 and the inventive compounds conform toFormula IIa or Formula IVa, respectively:

Alternatively, in certain embodiments variable “Y” in Formula I is —O—,—S—, —C(O)—, sulfoxide, sulfone, —CHR⁹— or —CH₂—, “n” is 2 or 3 and theinventive compounds conform to Formula IIIb and Formula IVb,respectively: When “Y” is —CHR⁹— in Formula IIIb or Formula IVb,substituent R⁹ is either hydrogen, lower alkyl or hydroxy.

For compounds according to Formulae IIa, IIb, IIIa, IIIb, IVa and IVb,variables W¹ and W² are both oxo. In certain embodiments for compoundsaccording to Formulae IIa, IIb, IIa, IIIb, IVa and IVb, W¹ is oxo and W²is thione group. According to one embodiment, Formulae IIa, IIb, IIIa,IIIb, IVa and IVb compounds comprise an oxo at W¹ and a ═N—OR′ group atW². Also encompassed within the scope of the present invention areFormulae IIa, IIb, IIIa, IIIb, IVa and IVb compounds having a thionegroup at W¹ and an oxo group at W².

For Formulae IIa, IIb, IIIa, IIIb, IVa and IVb compounds, each ofsubstituents R² and R³ can be the same in which case the carbon atomwhich R² and R³ are attached is not a chiral carbon. In certainembodiments, however, substituents R² and R³ are different. Thus, thecarbon atom which R² and R³ are attached is chiral and the resultingcompound will have stereoisomers.

In an embodiment of the invention, each R² and R³ in Formulae IIa, IIb,IIIa, IIIb, IVa and IVb is hydrogen. Alternatively, one of R² or R³groups in Formulae IIa, IIb, IIIa, IIIb, IVa and IVb is hydrogen and theother group is alkyl optionally substituted with 1, 2 or 3 J groups. Forcertain compounds according to Formulae IIa, IIb, IIIa, IIIb, IVa andIVb, R² and R³ are both alkyl groups that are optionally substitutedwith 1, 2 or 3 J groups.

For some compounds in accordance with Formula IIa or Formula IIb, R² isalkyl and R³ is alkyl substituted with 1, 2 or 3 J groups. Exemplary ofthis category of Formula IIa and Formula IIb compounds are thefollowing—compounds with substituent R² as alkyl and R³ is haloalkyl;compounds with substituent compounds with substituent R² as alkyl and R³is cycloalkyl optionally substituted with 1, 2 or 3 J groups; compoundswith substituent R² as alkyl and R³ is cyclopentyl optionallysubstituted with 1, 2 or 3 J groups; compounds with substituent R² asalkyl and R³ is aryl optionally substituted with 1, 2 or 3 J groups;compounds with substituent R² as alkyl and R³ is phenyl optionallysubstituted with 1, 2 or 3 J groups; compounds with substituent R² asalkyl and R³ is cycloalkylalkylene optionally substituted with 1, 2 or 3J groups; compounds with substituent R² as alkyl and R³ is aralkyleneoptionally substituted with 1, 2 or 3 J groups; compounds withsubstituent R² as alkyl and R³ is benzyl optionally substituted with 1,2 or 3 J groups; compounds with substituent R² as alkyl and R³ isheterocyclyl optionally substituted with 1, 2 or 3 J groups; compoundswith substituent R² as alkyl and R³ is heteroaryl optionally substitutedwith 1, 2 or 3 J groups; compounds with substituent R² as alkyl and R³is thiophenyl, thiazolyl or pyridinyl; compounds with substituent R² asalkyl and R³ is heterocyclylalkylene substituted or substituted with 1,2 or 3 J groups; or compounds with substituent R² as alkyl and R³ isheteroarylalkylene optionally substituted with 1, 2 or 3 J groups.

In one embodiment, for compounds according to Formulae IIa, IIb, IIIa,IIIb, IVa and IVb each R² and R³ are independently hydrogen, alkyl,cycloalkyl, cycloalkylalkylene, heterocyclyl or heterocyclylalkylene,and any such alkyl, cycloalkyl, cycloalkylalkylene, heterocyclyl orheterocyclylalkylene can optionally be substituted with 1, 2 or 3 Jgroups, independently selected from the group consisting of halogen,amino, alkylaminyl and alkyl.

For certain Formulae IIIa, IIIb, IVa and IVb compounds, R² and R³together with the carbon atom to which they are attached form acycloalkyl or heterocyclyl ring.

Also contemplated are Formula I compounds where Y is —N(R⁵)—, subscript“n” is 1 and R² and R³ together with the carbon atom to which they areattached form a cycloalkyl or heterocyclyl ring “A”. Such compoundsconform to Formula Va and the cycloalkyl or heterocyclyl ring “A” mayoptionally be substituted with 1, 2 or 3 J groups.

Alternatively, in some embodiments Y in Formula I is —O—, —S—, —C(O)—,sulfoxide, sulfone, —CHR⁹— or —CH₂—, “n” is 1 and R² and R³ togetherwith the carbon atom to which they are attached form a cycloalkyl orheterocyclyl ring A. Such compounds conform to Formula Vb and thecycloalkyl or heterocyclyl ring “A” may optionally be substituted with1, 2 or 3 J groups. When “Y” is —CHR⁹— in Formula Vb, substituent R⁹ iseither hydrogen, lower alkyl or hydroxy.

For Formula Va and Formula Vb compounds W¹ and W² are both oxo and ringA is a cycloalkyl optionally substituted with 1, 2 or 3 J groups. Alsocontemplated are Formula Va and Formula Vb compounds for which ring A isa fused cycloalkyl optionally substituted with 1, 2 or 3 J groups; ringA is a cycloalkyl optionally substituted with 1, 2 or 3 J groups; ring Ais a cyclobutyl, cyclopentyl or cyclohexyl optionally substituted with1, 2 or 3 J groups, for example, J groups selected from the groupconsisting of halogen, amino, alkylaminyl and alkyl.

For some embodiments, ring A of a Formula Va or a Formula Vb is aheterocyclyl optionally substituted with 1, 2 or 3 J groups. Exemplaryof such heterocyclyl groups are pyrrolidinyl, piperidinyl,tetrahydropyranyl, thietanyl or azetidinyl. In one embodiment, each ofthe above exemplified heterocyclyl may optionally be substituted with 1,2 or 3 J groups. For certain Formula Va or a Formula Vb compounds ring Ais a cycloalkyl substituted with at least 2J groups attached to the samecarbon atom of the cycloalkyl, and the two J groups attached to the samecarbon taken together form oxo group. In another embodiment, ring A of aFormula Va or a Formula Vb is a heterocyclyl substituted with at least2J groups that are attached to the same hetero atom and wherein such 2 Jgroups taken together to form oxo. For some Formula Va or a Formula Vbcompounds the cycloalkyl or heterocyclyl ring A is substituted with Jgroups selected from the group consisting of halogen, cyano, hydroxy,trifluoromethyl, N-methyl amino, methyl, difluoroethylene, andmethylenenitrile.

The present invention also provides compounds in accordance with FormulaVI or its stereoisomers, tautomers or pharmaceutically acceptable salts.Formula VI is a sub-genus of Formula I in which Y is —N(R⁵)— andsubstituent groups R⁵ and R⁸ together with the atoms to which they areattached form a heterocycle ring B which may optionally be substitutedwith 1, 2 or 3 J groups.

Also encompassed within the scope of the present invention are Formula Icompounds in which variable “Y” is —N(R⁵)—, and substituent groups R⁷and R⁸ together with the atoms to which they are attached form a fusedring C. Such compounds or the stereoisomer, tautomer or pharmaceuticallyacceptable salt conform to Formula VIIa. For Formula VIIa compounds ringC may optionally be substituted with 1, 2 or 3 J groups.

According to one embodiment, variable “Y” in Formula I is —O—, —S—,—C(O)—, sulfoxide, sulfone, —CHR⁹— or —CH₂—, and substituent groups R⁷and R⁸ together with the atoms to which they are attached form a fusedring C. Such compounds and their stereoisomers, tautomers orpharmaceutically acceptable salts conform to Formula VIIb. For FormulaVIIb compounds where “Y” is —CHR⁹—, substituent R⁹ can be hydrogen,lower alkyl or hydroxy.

For Formula VIIb compounds fused ring C may optionally be substitutedwith 1, 2 or 3 J groups. In one embodiment of the invention, W¹ and W²are both oxo for Formula VI, Formula VIIa and Formula VIIb compounds.

The present invention is further directed to Formulae I, Ia, IIa, IIb,IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb compounds where R¹ ishydrogen or a lower alkyl group selected from methyl, ethyl, propyl,butyl, iso-propyl, sec-butyl, or tert-butyl, for example, compounds withR¹ as methyl.

For certain Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI,VIIa and VIIb compounds, R^(4a) is selected from the group consisting ofhydrogen, halogen, alkyl, alkoxy, thioalkyl, alkenyl, and cycloalkylwhile substituent R^(4b) is hydrogen or halogen. R⁵ in Formulae I, Ia,IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb, VI, VIIa and VIIb is hydrogen orlower alkyl, while substituents R⁶, R⁷ and R⁸ are hydrogen.

In an embodiment of the invention, R⁶ and R⁷ in Formula VI are bothhydrogen, while for certain Formula VIIa and Formula VIIb compounds R⁶is hydrogen.

The present invention is further directed to Formulae I, Ia, IIa, IIb,IIIa, IIIb, IVa, IVb, Va, and Vb compounds where substituent groups R⁶and R⁸ are both hydrogen, and R₇ is selected from the group consistingof hydroxy, halogen, cyano, alkyl, alkenyl, alkynyl, alkoxy, cycloalkylcycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl,alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl,heterocyclylaminyl, heteroaryl, and heterocyclyl. For these inventivecompounds any alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl,alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl,heterocyclylaminyl, heteroaryl, or heterocyclyl is optionallysubstituted with 1, 2 or 3 J groups. In one embodiment R₇ is selectedfrom the group consisting of alkyl, cycloalkyl, cycloalkylalkylene,cycloalkylalkenylene, amino, alkylaminyl, alklycarbonylaminyl,cycloalkylcarbonylaminyl, heterocyclylaminyl, heteroaryl, heterocyclyland cycloalkylaminyl. For such compounds any alkyl, alkenyl, cycloalkyl,cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl,alklycarbonylaminyl, cycloalkylcarbonylaminyl, heterocyclylaminyl,heteroaryl, heterocyclyl or cycloalkylaminyl may optionally besubstituted with 1, 2 or 3 J groups. Thus, the invention providesFormulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, and Vb compoundswhere substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is amino;substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is alkylaminyl;substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is —NHCH₃;substituent groups R⁶ and R⁸ are both hydrogen, and R₇ is cycloalkyl,for example cyclopropyl; substituent groups R⁶ and R⁸ are both hydrogen,and R₇ is cycloalkylaminyl substituted with 1 to 3 J groups, forinstance halogens.

In one embodiment, for compounds in accordance with Formulae I, Ia, IIa,IIb, IIIa, IIIb, IVa, IVb, Va, and Vb, substituent groups R⁶ and R⁸ areboth hydrogen, and R₇ is selected from the group consisting of—NHCH(CF₃)cyclopropyl, cycloalkylcarbonylaminyl, —NHC(O)cyclopropyl,cycloalkylalkenylene, and CH═CHcyclopropyl.

For any compound in accordance with Formulae I, Ia, IIa, IIb, IIIa,IIIb, IVa, IVb, Va, Vb, VI, VIIa, and VIIb, J is —SH, —SR⁹, —S(O)R⁹,—S(O)₂ R⁹, —S(O)NH₂, —S(O)NR⁹R⁹, —NH₂, —NR⁹R⁹, —COOH, —C(O)OR⁹, —C(O)R⁹,—C(O)—NH₂, —C(O)—NR⁹R⁹, hydroxy, cyano, halogen, acetyl, alkyl, loweralkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene,alkylaminyl, NH₂—C(O)-alkylene, NR⁹R⁹—C(O)-alkylene, —CHR⁹—C(O)-loweralkyl, —C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl,cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl,cycloalkylaminyl, —CHR⁹—C(O)-cycloalkyl, —C(O)-cycloalkyl,—CHR⁹—C(O)-aryl, —CHR⁹-aryl, —C(O)-aryl, —CHR⁹—C(O)-heterocycloalkyl,—C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl and R⁹ ishydrogen, lower alkyl or —OH. Additionally, when two J groups bound tothe same carbon or hetero atom they may be taken together to form oxo.

For certain compounds according to Formulae I, Ia, IIa, IIb, IIIa, IIIb,IVa, IVb, Va, Vb, VI, VIIa, and VIIb, J is halogen, hydroxy, alkyl,alkenyl, alkynyl or cyanoalkylene. Illustrative alkyl or alkylene chainsare those having C₁-C₁₀ carbon atoms, C₁-C₈ carbon atoms, C₁-C₆ carbonatoms, C₁-C₄ carbon atoms, C₁-C₃ carbon atoms as well as ethyl andmethyl groups. Alternatively, when J is alkenyl, or alkynyl, the carbonchain has at least one double or triple bond respectively and C₂-C₁₀carbon atoms, C₂-C₈ carbon atoms, C₂-C₆ carbon atoms, C₂-C₄ carbonatoms, or C₂-C₃ carbon atoms.

The inventive compounds according to Formula I, as well as Formulae Ia,IIa, IIb, IIa, IIIb, IVa, IVb, Va, Vb VI, VIIa and VIIb may beisotopically-labelled by having one or more atoms replaced by an atomhaving a different atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of according to Formula I includeisotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,chlorine, or iodine. Illustrative of such isotopes are ²H, ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I,respectively. These radiolabelled compounds can be used to measure thebiodistribution, tissue concentration and the kinetics of transport andexcretion from biological tissues including a subject to which such alabelled compound is administered. Labeled compounds are also used todetermine therapeutic effectiveness, the site or mode of action, and thebinding affinity of a candidate therapeutic to a pharmacologicallyimportant target. Certain radioactive-labelled compounds according toFormula I, therefore, are useful in drug and/or tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, affordscertain therapeutic advantages resulting from the greater metabolicstability, for example, increased in vivo half-life of compoundscontaining deuterium. Substitution of hydrogen with deuterium may reducedose required for therapeutic effect, and hence may be preferred in adiscovery or clinical setting.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, provides labeled analogs of the inventive compounds that are usefulin Positron Emission Tomography (PET) studies, e.g., for examiningsubstrate receptor occupancy. Isotopically-labeled compounds accordingto Formula I, as well as Formulae Ia, IIa, IIb, IIIa, IIIb, IVa, IVb,Va, Vb VI, VIIa and VIIb can generally be prepared by conventionaltechniques known to those skilled in the art or by processes analogousto those described in the Preparations and Examples section as set outbelow using an appropriate isotopic-labeling reagent.

Embodiments of the invention disclosed herein are also meant toencompass the in vivo metabolic products of compounds according toFormulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb VI, VIIa andVIIb. Such products may result from, for example, the oxidation,reduction, hydrolysis, amidation, esterification, and like processesprimarily due to enzymatic activity upon administration of a compound ofthe invention. Accordingly, the invention includes compounds that areproduced as by-products of enzymatic or non-enzymatic activity on aninventive compound following the administration of such a compound to amammal for a period of time sufficient to yield a metabolic product.Metabolic products, particularly pharmaceutically active metabolites aretypically identified by administering a radiolabelled compound of theinvention in a detectable dose to a subject, such as rat, mouse, guineapig, monkey, or human, for a sufficient period of time during whichmetabolism occurs, and isolating the metabolic products from urine,blood or other biological samples that are obtained from the subjectreceiving the radiolabelled compound.

The invention also provides pharmaceutically acceptable salt forms ofFormulae I, Ia, IIa, IIb, IIIa, IIIb, IVa, IVb, Va, Vb VI, VIIa and VIIbcompounds. Encompassed within the scope of the invention are both acidand base addition salts that are formed by contacting a pharmaceuticallysuitable acid or a pharmaceutically suitable base with a compound of theinvention.

To this end, a “pharmaceutically acceptable acid addition salt” refersto those salts which retain the biological effectiveness and propertiesof the free bases, which are not biologically or otherwise undesirable,and which are formed with inorganic acids such as, but are not limitedto, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid and the like, and organic acids such as, but not limitedto, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid,ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid,4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid,capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid,citric acid, cyclamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonicacid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid,fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid,gluconic acid, glucuronic acid, glutamic acid, glutaric acid,2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuricacid, isobutyric acid, lactic acid, lactobionic acid, lauric acid,maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonicacid, mucic acid, naphthalene-1,5-disulfonic acid,naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid,oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid,propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid,4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid,tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroaceticacid, undecylenic acid, and the like.

Similarly, a “pharmaceutically acceptable base addition salt” refers tothose salts which retain the biological effectiveness and properties ofthe free acids, which are not biologically or otherwise undesirable.These salts are prepared by addition of an inorganic base or an organicbase to the free acid. Salts derived from inorganic bases include, butare not limited to, the sodium, potassium, lithium, ammonium, calcium,magnesium, iron, zinc, copper, manganese, aluminum salts and the like.Preferred inorganic salts are the ammonium, sodium, potassium, calcium,and magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as ammonia,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, diethanolamine, ethanolamine, deanol,2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine,lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline,betaine, benethamine, benzathine, ethylenediamine, glucosamine,methylglucamine, theobromine, triethanolamine, tromethamine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins and thelike. Particularly preferred organic bases are isopropylamine,diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, cholineand caffeine.

Often crystallizations produce a solvate of the compound of theinvention. As used herein, the term “solvate” refers to an aggregatethat comprises one or more molecules of a compound of the invention withone or more molecules of solvent. The solvent may be water, in whichcase the solvate may be a hydrate. Alternatively, the solvent may be anorganic solvent. Thus, the compounds of the present invention may existas a hydrate, including a monohydrate, dihydrate, hemihydrate,sesquihydrate, trihydrate, tetrahydrate and the like, as well as thecorresponding solvated forms. The compounds of the invention may be truesolvates, while in other cases, the compounds of the invention maymerely retain adventitious water or be a mixture of water plus someadventitious solvent.

A “stereoisomer” refers to a compound made up of the same atoms bondedby the same bonds but having different three-dimensional structures,which are not interchangeable. The present invention contemplatesvarious stereoisomers and mixtures thereof and includes “enantiomers”,which refers to two stereoisomers whose molecules are nonsuperimposeablemirror images of one another.

Compounds of the invention, or their pharmaceutically acceptable saltsmay contain one or more asymmetric centers and may thus give rise toenantiomers, diastereomers, and other stereoisomeric forms that may bedefined, in terms of absolute stereochemistry, as (R)- or (S)- or, as(D)- or (L)- for amino acids. The present invention is meant to includeall such possible isomers, as well as their racemic and optically pureforms. Optically active (+) and (−), (R)- and (S)-, or (D)- and(L)-isomers may be prepared using chiral synthons or chiral reagents, orresolved using conventional techniques, for example, chromatography andfractional crystallization. Conventional techniques for thepreparation/isolation of individual enantiomers include chiral synthesisfrom a suitable optically pure precursor or resolution of the racemate(or the racemate of a salt or derivative) using, for example, chiralhigh pressure liquid chromatography (HPLC). When the compounds describedherein contain olefinic double bonds or other centers of geometricasymmetry, and unless specified otherwise, it is intended that thecompounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

The term “tautomer” refers to a proton shift from one atom of a moleculeto another atom of the same molecule. For example, when W′ is oxo and R¹is H, the present invention provides tautomers of a Formula I compoundas illustrated below:

Similar tautomers exists for Formulae I, Ia, IIa, IIb, IIIa, IIIb, IVa,IVb, Va, Vb VI, VIIa and VIIb compounds. The inventive compounds aresynthesized using conventional synthetic methods, and more specificallyusing the general methods noted below. Specific synthetic protocols forseveral compounds in accordance with the present invention are describedin the Examples.

General Synthetic Methods Method 1:

Formation of IXa, when n=1 and X=halogen or other leaving group, such as—OTf, —OTs or —OMs, was accomplished by exposing intermediate VIIIa toan aldehyde or ketone Xa, or an aldehyde or ketone equivalent Xb-d underacidic conditions where R²-R³ are as previously defined and R^(m)=H,CH₃, CH₂CH₃, or alkyl. More specifically, exposing VIIIa where X is Clor Br to an aldehyde or ketone Xa in 1,4-dioxane and concentratedsulfuric acid with heating yields intermediated IXa (n=1).

Pyrimidine-type compounds according to Formula XIIa or XIIb where Y isN(R⁵), O, or S and P is a protecting group can be purchased or preparedfrom XIa by various methods, for example, by displacing the leavinggroup X of compound XIa with an appropriate N, O, or S nucleophile. Theresulting compound XIIb can be deprotected to give XIIa.

Inventive compounds according to Formula I when Y is N(R⁵), O, or S weresynthesized by contacting intermediate IXa with a pyrimidine compoundXIIa where R⁶-R⁸ are as previously defined, under appropriate reactionconditions as further described below.

More specifically, Formula I compounds when Y is N(R⁵), O, or S weresynthesized using Buchwald-Hartwig coupling, Ullmann-type coupling, ornucleophilic aromatic substitution. Thus, contacting intermediate IXawhere X=Cl or Br and n=1 with a compound of Formula XIIa where Y isN(R⁵), O, or S under conditions suitable for coupling, or nucleophilicaromatic substitution gave Formula I compounds.

Alternatively, the leaving group X of intermediate IXa may be displacedwith an appropriate N, O, or S nucleophile under conditions similar tothose described above for synthesis of XIIa so as to afford intermediateXIIIa or protected intermediate XIIIb where Y is N(R⁵), O, or S. XIIIbmay be deprotected to yield XIIIa.

Formula I compounds when Y is N(R⁵), O, or S are readily synthesized bycontacting intermediate XIIIa where Y is N(R⁵), O, or S with apyrimidine compound XIa where X=halogen or other leaving group such as—OTf, —OTs or —OMs under the conditions of Buchwald-Hartwig coupling,Ullmann-type coupling, or nucleophilic aromatic substitution.

More specific synthetic methods for several Formula I compounds are setforth below. It is understood that if protecting groups are used duringthe synthesis of intermediates, or if a Formula I compound contains oneor more protecting groups, then such protecting groups are removed bymethods known in the chemical art. Other transformations, such as thedisplacement of a halogen, for example, the conversion of R^(4a), orR^(4b)=Cl to R^(4a), or R^(4b)=OMe, SMe, CH═CH₂ or Me, the conversion ofW¹, or W² or both groups from O to S; the formation of an oxime byconverting W¹, or W² or both groups from an oxo (═O) group to a ═NHOR′group, the conversion of Y from S to S═O or S(═O)₂, and the conversionof an intermediate or a Formula I compound to a pharmaceuticallyacceptable salt are carried out using conventional methods known in thechemical art.

Method 2:

Formation of IXa or IXb, when n=2 or 3, variable “X” is a halogen oranother leaving group such as —OTf, —OTs or —OMs, and variable “V” is Oor N can be accomplished by contacting intermediate VIIIb to a1,2-difunctionalized ethyl intermediate XIVa, or a 1,3-difunctionalizedpropyl intermediate XIVb under conditions suitable for the synthesis ofcompounds IXa and IXb respectively. Variables Z¹ and Z² in XIVa and XIVbcan be a halogen or other leaving groups such as —OTf, —OTs or —OMs, orOH, NHR¹ or NHP, where P is an appropriate protecting group.

According to this synthetic strategy, intermediate VIIIb where variable“X” is Cl or Br and variable “V” is O is contacted with XIVa where R²and R³ are H, Z¹ is OH and Z² is NH-(4-methoxybenzyl) in acetonitrile inthe presence of an amide bond forming reagent such as HATU. The reactionmixture is heated to promote coupling and yields intermediated IXb wheren=2 and P is 4-methoxybenzyl.

The inventive Formula I compounds when Y is N(R⁵), O, or S aresynthesized by contacting intermediates IXa or IXb (n=2 or 3 andX=halogen or other leaving group such as —OTf, —OTs or —OMs), withpyrimidine XIIa where Y is N(R⁵), O, or S and R⁶-R⁸ are as previouslydefined, under appropriate conditions followed by deprotection of theresultant Formula I compound if required.

Thus, contacting intermediate DO where n=2, X is Cl or Br and P is4-methoxybenzyl with pyrimidine XIIa, where Y is N(R⁵), O, or S, underthe conditions suitable for Buchwald-Hartwig coupling, Ullmann-typecoupling, or nucleophilic aromatic substitution results in a4-methoxybenzyl protected Formula I compound. The therapeutically activeFormula I compound can readily be obtained by deprotection of the4-methoxybenzyl group with trifluoroacetic acid.

Alternatively, certain Formula I compounds were synthesized bydisplacing the leaving group “X” of intermediate IXa with suitable N, O,or S nucleophiles under similar conditions similar to those described inMethod 1 to give XIIIa or protected intermediate XIIIb which can bedeprotected to yield XIIIa. The leaving group “X” of intermediate IXacan be halogen, —OTf, —OTs or —OMs and subscript n is either 2 or 3.

As described above, the inventive Formula I compounds are readilysynthesized by contacting intermediate XIIIa when Y=N(R⁵), O, S and n=2or 3 with pyrimidine XIa where X=halogen, —OTf, —OTs or —OMs underconditions suitable for Buchwald-Hartwig coupling, Ullmann-typecoupling, or nucleophilic aromatic substitution.

The synthesis of some Formula I compounds was carried out by contactingthe protected intermediate IXb (n=2 or 3), with an appropriate N, O, orS nucleophile to give XIIIc under similar conditions described abovewith IXa.

Intermediate XIIIc, thus obtained, was then contacted with pyrimidineXIa where X is either halogen or a leaving group selected from the groupconsisting of —OTf, —OTs and —OMs under conditions suitable forBuchwald-Hartwig coupling, Ullmann-type coupling, or nucleophilicaromatic substitution. Deprotection by methods known in the chemical artgave the candidate MnK inhibitor Formula I compounds.

Method 3:

Synthesis of Formula VI compounds, where n=1, 2, or 3 was accomplishedby contacting intermediates IXa or IXb where variable “X” is a leavinggroup selected from the group consisting of halogen, —OTf, —OTs and—OMs, and P is a protecting group with a bicyclic intermediate XV in thepresence of a homogeneous palladium-phosphine catalyst and a base suchas cesium carbonate or sodium t-butoxide using 1,4-dioxane as a solvent.The reaction mixture was heated to promote coupling, followed bydeprotection if needed. Illustrative of intermediate XV compoundswithout limitation are substituted or unsubstituted6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine,9H-purine, 1H-pyrazolo[3,4-d]pyrimidine, and5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine).

Alternatively, Formula VI compounds where B is an unsaturated 5-memberedring and n=1, 2 or 3 may be synthesized by contacting intermediates IXaor IXb with a 5-ethynyl-4-amino-pyrimidine intermediate XIIc (whereR^(a) is a J group as defined herein) in the presence of a homogeneouspalladium-phosphine catalyst and a base such as cesium carbonate orsodium t-butoxide using 1,4-dioxane as solvent for the couplingreaction. The reaction mixture may be heated to promote coupling,followed by deprotection if required. The 5-Ethynyl-4-amino-pyrimidineintermediates XIIc synthesized by a cross-coupling reaction between XIIawhere Y=N(R⁵) and R⁸ is a leaving group such as halogen or —OTf and asuitable alkyne using copper and/or homogeneous palladium catalysts.

Method 4:

Compounds according to Formula VIIa or Formula VIIb, where Y=N(R⁵), O,or S and n is 1, 2 or 3 can be synthesized by contacting intermediatesIXa or IXb where X is a leaving group such as halogen, —OTf, —OTs or—OMs, and P is a protecting group with the bicyclic intermediate XVIaunder the conditions of Buchwald-Hartwig coupling, Ullmann-typecoupling, or nucleophilic aromatic substitution. Ring C of bicyclicintermediate is as defined above and variable Y can be —N(R⁵), O, or S.Representative examples of XVIa intermediates include without limitationsubstituted or unsubstituted 6-amino-purine,4-amino-1H-pyrazolo[3,4-d]pyrimidine,4-amino-7H-pyrrolo[2,3-d]pyrimidine,4-amino-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine,7-amino-3H-[1,2,3]triazolo[4,5-d]pyrimidine, 4-aminoquinazoline,4-amino-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidine, various4-amino-pyrido[d]pyrimidines, pyrimido[5,4-d]pyrimidin-4-amine, and7,8-dihydro-6H-pyrimido[5,4-b][1,4]oxazin-4-amine).

Bicyclic pyrimidine-type intermediate compounds according to FormulaXVIa where Y=N(R⁵), O, or S can be purchased or prepared from XVI bydisplacing the leaving group X with an appropriate N, O, or Snucleophile using methods known in the chemical art. The protectinggroup “P” in an intermediate according to XVIb can be removed to giveintermediate XVIa.

Alternatively intermediates XIIIa or XIIIb may be contacted with thefused pyrimidine XVI where X=halogen or other leaving group such as—OTf, —OTs or —OMs under conditions suitable for Buchwald-Hartwig orUllmann-type couplings, or conditions suitable for nucleophilic aromaticsubstitution followed by deprotection if necessary to give Formula VIIaor Formula VIIb compounds.

Method 5:

Methods for synthesizing a Formula I, when Y is —C(O) and n=1, 2 or 3comprise contacting intermediate IXa or intermediate DO (where X is aleaving group, such as halogen, —OTf, —OTs or —OMs, and P is aprotecting group) with the intermediate XIId in the presence of a basesuch as n-butyllithium. The resultant product may be deprotected ifrequired to provide Formula I compounds.

Formation of Formula I, where Y=CH and n=1, 2 or 3 may be carried out byreducing the carbonyl (—C(O)) at “Y” under Wolff-Kishner reductionconditions.

Method 6:

Synthesis of Formula VIIb compounds, when Y=C(O), n=1, 2 or 3 and C isas defined previously is carried out by contacting intermediate IXa orintermediate IXb (where X is a leaving group, such as halogen, —OTf,—OTs or —OMs, and P is a protecting group) with the intermediate XVIc inthe presence of a base such as n-butyllithium. The resultant product maybe deprotected if required to provide Formula VIIb compounds.

Formation of VIIb, when Y=CH and n=1, 2 or 3 may be accomplished byreducing the carbonyl (—C(O)) at “Y” under Wolff-Kishner reductionconditions.

Pharmaceuticals Formulations

In one embodiment, a compounds according Formulae I through VII, areformulated as pharmaceutically acceptable compositions that contain aFormulae I-VII compound in an amount effective to treat a particulardisease or condition of interest upon administration of thepharmaceutical composition to a mammal. Pharmaceutical compositions inaccordance with the present invention can comprise a Formulae I-VIIcompound in combination with a pharmaceutically acceptable carrier,diluent or excipient.

In this regard, a “pharmaceutically acceptable carrier, diluent orexcipient” includes without limitation any adjuvant, carrier, excipient,glidant, sweetening agent, diluent, preservative, dye/colorant, flavorenhancer, surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

Further, a “mammal” includes humans and both domestic animals such aslaboratory animals and household pets (e.g., cats, dogs, swine, cattle,sheep, goats, horses, rabbits), and non-domestic animals such aswildlife and the like.

The pharmaceutical compositions of the invention can be prepared bycombining a compound of the invention with an appropriatepharmaceutically acceptable carrier, diluent or excipient, and may beformulated into preparations in solid, semi-solid, liquid or gaseousforms, such as tablets, capsules, powders, granules, ointments,solutions, suppositories, injections, inhalants, gels, microspheres, andaerosols. Typical routes of administering such pharmaceuticalcompositions include, without limitation, oral, topical, transdermal,inhalation, parenteral, sublingual, buccal, rectal, vaginal, andintranasal. The term parenteral as used herein includes subcutaneousinjections, intravenous, intramuscular, intrasternal injection orinfusion techniques. Pharmaceutical compositions of the invention areformulated so as to allow the active ingredients contained therein to bebioavailable upon administration of the composition to a patient.Compositions that will be administered to a subject or patient take theform of one or more dosage units, where for example, a tablet may be asingle dosage unit, and a container of a compound of the invention inaerosol form may hold a plurality of dosage units. Actual methods ofpreparing such dosage forms are known, or will be apparent, to thoseskilled in this art; for example, see Remington: The Science andPractice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy andScience, 2000). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease or condition of interest in accordance with the teachingsof this invention.

A pharmaceutical composition of the invention may be in the form of asolid or liquid. In one aspect, the carrier(s) are particulate, so thatthe compositions are, for example, in tablet or powder form. Thecarrier(s) may be liquid, with the compositions being, for example, anoral syrup, injectable liquid or an aerosol, which is useful in, forexample, inhalatory administration. When intended for oraladministration, the pharmaceutical composition is preferably in eithersolid or liquid form, where semi-solid, semi-liquid, suspension and gelforms are included within the forms considered herein as either solid orliquid.

As a solid composition for oral administration, the pharmaceuticalcomposition may be formulated into a powder, granule, compressed tablet,pill, capsule, chewing gum, wafer or the like form. Such a solidcomposition will typically contain one or more inert diluents or ediblecarriers. In addition, one or more of the following may be present:binders such as carboxymethylcellulose, ethyl cellulose,microcrystalline cellulose, gum tragacanth or gelatin; excipients suchas starch, lactose or dextrins, disintegrating agents such as alginicacid, sodium alginate, Primogel, corn starch and the like; lubricantssuch as magnesium stearate or Sterotex; glidants such as colloidalsilicon dioxide; sweetening agents such as sucrose or saccharin; aflavoring agent such as peppermint, methyl salicylate or orangeflavoring; and a coloring agent.

When the pharmaceutical composition is in the form of a capsule, forexample, a gelatin capsule, it may contain, in addition to materials ofthe above type, a liquid carrier such as polyethylene glycol or oil.

The pharmaceutical composition may be in the form of a liquid, forexample, an elixir, syrup, solution, emulsion or suspension. The liquidmay be for oral administration or for delivery by injection, as twoexamples. When intended for oral administration, preferred compositioncontain, in addition to the present compounds, one or more of asweetening agent, preservatives, dye/colorant and flavor enhancer. In acomposition intended to be administered by injection, one or more of asurfactant, preservative, wetting agent, dispersing agent, suspendingagent, buffer, stabilizer and isotonic agent may be included.

The liquid pharmaceutical compositions of the invention, whether they besolutions, suspensions or other like form, may include one or more ofthe following adjuvants: sterile diluents such as water for injection,saline solution, preferably physiological saline, Ringer's solution,isotonic sodium chloride, fixed oils such as synthetic mono ordiglycerides which may serve as the solvent or suspending medium,polyethylene glycols, glycerin, propylene glycol or other solvents;antibacterial agents such as benzyl alcohol or methyl paraben;antioxidants such as ascorbic acid or sodium bisulfate; chelating agentssuch as ethylenediaminetetraacetic acid; buffers such as acetates,citrates or phosphates and agents for the adjustment of tonicity such assodium chloride or dextrose. The parenteral preparation can be enclosedin ampoules, disposable syringes or multiple dose vials made of glass orplastic. Physiological saline is a preferred adjuvant. An injectablepharmaceutical composition is preferably sterile.

A liquid pharmaceutical composition of the invention intended for eitherparenteral or oral administration should contain an amount of a compoundof the invention such that a suitable dosage will be obtained.

The pharmaceutical composition of the invention may be intended fortopical administration, in which case the carrier may suitably comprisea solution, emulsion, ointment or gel base. The base, for example, maycomprise one or more of the following: petrolatum, lanolin, polyethyleneglycols, bee wax, mineral oil, diluents such as water and alcohol, andemulsifiers and stabilizers. Thickening agents may be present in apharmaceutical composition for topical administration. If intended fortransdermal administration, the composition may include a transdermalpatch or iontophoresis device.

The pharmaceutical composition of the invention may be intended forrectal administration, in the form, for example, of a suppository, whichwill melt in the rectum and release the drug. The composition for rectaladministration may contain an oleaginous base as a suitablenonirritating excipient. Such bases include, without limitation,lanolin, cocoa butter and polyethylene glycol.

The pharmaceutical composition of the invention may include variousmaterials, which modify the physical form of a solid or liquid dosageunit. For example, the composition may include materials that form acoating shell around the active ingredients. The materials that form thecoating shell are typically inert, and may be selected from, forexample, sugar, shellac, and other enteric coating agents.Alternatively, the active ingredients may be encased in a gelatincapsule.

The pharmaceutical composition of the invention in solid or liquid formmay include an agent that binds to the compound of the invention andthereby assists in the delivery of the compound. Suitable agents thatmay act in this capacity include a monoclonal or polyclonal antibody, aprotein or a liposome.

The pharmaceutical composition of the invention may consist of dosageunits that can be administered as an aerosol. The term aerosol is usedto denote a variety of systems ranging from those of colloidal nature tosystems consisting of pressurized packages. Delivery may be by aliquefied or compressed gas or by a suitable pump system that dispensesthe active ingredients. Aerosols of compounds of the invention may bedelivered in single phase, bi-phasic, or tri-phasic systems in order todeliver the active ingredient(s). Delivery of the aerosol includes thenecessary container, activators, valves, subcontainers, and the like,which together may form a kit. One skilled in the art, without undueexperimentation may determine preferred aerosols.

The pharmaceutical compositions of the invention may be prepared by anymethodology well known in the pharmaceutical art. For example, apharmaceutical composition intended to be administered by injection canbe prepared by combining a compound of the invention with sterile,distilled water so as to form a solution. A surfactant may be added tofacilitate the formation of a homogeneous solution or suspension.Surfactants are compounds that non-covalently interact with the compoundof the invention so as to facilitate dissolution or homogeneoussuspension of the compound in the aqueous delivery system.

In certain embodiments a pharmaceutical composition comprising acompound of Formula I is administered to a mammal in an amountsufficient to inhibit Mnk activity upon administration, and preferablywith acceptable toxicity to the same. Mnk activity of Formula Icompounds can be determined by one skilled in the art, for example, asdescribed in the Examples below. Appropriate concentrations and dosagescan be readily determined by one skilled in the art.

Therapeutic Use

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount, whichwill vary depending upon a variety of factors including the activity ofthe specific compound employed; the metabolic stability and length ofaction of the compound; the age, body weight, general health, sex, anddiet of the patient; the mode and time of administration; the rate ofexcretion; the drug combination; the severity of the particular disorderor condition; and the subject undergoing therapy.

“Effective amount” or “therapeutically effective amount” refers to thatamount of a compound of the invention which, when administered to amammal, preferably a human, is sufficient to effect treatment, asdefined below, of a Mnk related condition or disease in the mammal,preferably a human. The amount of a compound of the invention whichconstitutes a “therapeutically effective amount” will vary depending onthe compound, the condition and its severity, the manner ofadministration, and the age of the mammal to be treated, but can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

Compounds of the invention, or pharmaceutically acceptable salt thereof,may also be administered simultaneously with, prior to, or afteradministration of one or more other therapeutic agents. Such combinationtherapy includes administration of a single pharmaceutical dosageformulation which contains a compound of the invention and one or moreadditional active agents, as well as administration of the compound ofthe invention and each active agent in its own separate pharmaceuticaldosage formulation. For example, a compound of the invention and theother active agent can be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent administered in separate oral dosage formulations. Where separatedosage formulations are used, the compounds of the invention and one ormore additional active agents can be administered at essentially thesame time, i.e., concurrently, or at separately staggered times, i.e.,sequentially; combination therapy is understood to include all theseregimens.

In certain embodiments, the disclosed compounds are useful forinhibiting the activity of Mnk and/or can be useful in analyzing Mnksignaling activity in model systems and/or for preventing, treating, orameliorating a symptom associated with a disease, disorder, orpathological condition involving Mnk, preferably one afflicting humans.A compound which inhibits the activity of Mnk will be useful inpreventing, treating, ameliorating, or reducing the symptoms orprogression of diseases of uncontrolled cell growth, proliferationand/or survival, inappropriate cellular immune responses, orinappropriate cellular inflammatory responses or diseases which areaccompanied with uncontrolled cell growth, proliferation and/orsurvival, inappropriate cellular immune responses, or inappropriatecellular inflammatory responses, particularly in which the uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune responses, or inappropriate cellular inflammatory responses ismediated by Mnk, such as, for example, haematological tumors, solidtumors, and/or metastases thereof, including leukaemias andmyelodysplastic syndrome, malignant lymphomas, for example, B-celllymphoma, T-cell lymphoma, hairy cell lymphoma, Hodgkins lymphoma,non-Hodgins lymphoma and Burkitts lymphoma, head and neck tumorsincluding brain tumors and brain metastases, tumors of the thoraxincluding non-small cell and small cell lung tumors, gastrointestinaltumors, endocrine tumors, mammary and other gynecological tumors,urological tumors including renal, bladder and prostate tumors, skintumors, and sarcomas, and/or metastases thereof.

Furthermore, the inventive compounds and their pharmaceuticalcompositions are candidate theraputics for the prophylaxis and/ortherapy of cytokine related diseases, such as inflammatory diseases,allergies, or other conditions associated with proinflammatorycytokines. Exemplary inflammatory diseases include without limitation,chronic or acute inflammation, inflammation of the joints such aschronic inflammatory arthritis, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, juvenile rheumatoid arthritis, Reiter'ssyndrome, rheumatoid traumatic arthritis, rubella arthritis, acutesynovitis and gouty arthritis; inflammatory skin diseases such assunburn, psoriasis, erythrodermic psoriasis, pustular psoriasis, eczema,dermatitis, acute or chronic graft formation, atopic dermatitis, contactdermatitis, urticaria and scleroderma; inflammation of thegastrointestinal tract such as inflammatory bowel disease, Crohn'sdisease and related conditions, ulcerative colitis, colitis, anddiverticulitis; nephritis, urethritis, salpingitis, oophoritis,endomyometritis, spondylitis, systemic lupus erythematosus and relateddisorders, multiple sclerosis, asthma, meningitis, myelitis,encephalomyelitis, encephalitis, phlebitis, thrombophlebitis,respiratory diseases such as asthma, bronchitis, chronic obstructivepulmonary disease (COPD), inflammatory lung disease and adultrespiratory distress syndrome, and allergic rhinitis; endocarditis,osteomyelitis, rheumatic fever, rheumatic pericarditis, rheumaticendocarditis, rheumatic myocarditis, rheumatic mitral valve disease,rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, inflammatory diseases of thethyroid selected from the group consisting of granulomatous thyroiditis,lymphocytic thyroiditis, invasive fibrous thyroiditis, acutethyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud'sphenomenon, Sjogren's syndrome, neuroinflammatory disease, sepsis,conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis,lymphoadenitis, nasopaharingitis, sinusitis, pharyngitis, tonsillitis,laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis,gingivitis. oesophagitis, gastritis, peritonitis, hepatitis,cholelithiasis, cholecystitis, glomerulonephritis, goodpasture'sdisease, crescentic glomerulonephritis, pancreatitis, endomyometritis,myometritis, metritis, cervicitis, endocervicitis, exocervicitis,parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.

Although inflammation is the unifying pathogenic process of thesediseases, current therapies only treat the symptoms of the disease andnot the underlying cause of inflammation. The compositions of thepresent invention are useful for the treatment and/or prophylaxis ofinflammatory diseases and related complications and disorders.

Accordingly, certain embodiments are directed to a method for treating aMnk dependent condition in a mammal in need thereof, the methodcomprising administering an effective amount of a pharmaceuticalcomposition as described above (i.e., a pharmaceutical compositioncomprising any one or more compounds of Formula I) to a mammal.

“Treating” or “treatment” as used herein covers the treatment of thedisease or condition of interest in a mammal, preferably a human, havingthe disease or condition of interest, and includes:

-   -   (i) preventing the disease or condition from occurring in a        mammal, in particular, when such mammal is predisposed to the        condition but has not yet been diagnosed as having it;    -   (ii) inhibiting the disease or condition, i.e., arresting its        development;    -   (iii) relieving the disease or condition, i.e., causing        regression of the disease or condition; or    -   (iv) relieving the symptoms resulting from the disease or        condition, i.e., relieving pain without addressing the        underlying disease or condition. As used herein, the terms        “disease” and “condition” may be used interchangeably or may be        different in that the particular malady or condition may not        have a known causative agent (so that etiology has not yet been        worked out) and it is therefore not yet recognized as a disease        but only as an undesirable condition or syndrome, wherein a more        or less specific set of symptoms have been identified by        clinicians.

As described above deregulation of protein synthesis is a common eventin human cancers. A key regulator of translational control is eIF4Ewhose activity is a key determinant of tumorigenicity. Becauseactivation of eIF4E involves phosphorylation of a key serine (Ser209)specifically by MAP kinase interacting kinases (Mnk), inhibitors of Mnkare suitable candidate therapeutics for treating cell proliferativedisorders such as cancer. A wide variety of cancers, including solidtumors, lymphomas and leukemias, are amenable to the compositions andmethods disclosed herein. Types of cancer that may be treated include,but are not limited to adenocarcinoma of the breast, prostate, andcolon; all forms of bronchogenic carcinoma of the lung; myeloid;melanoma; hepatoma; neuroblastoma; papilloma; apudoma; choristoma;branchioma; malignant carcinoid syndrome; carcinoid heart disease; andcarcinoma (e.g., Walker, basal cell, basosquamous, Brown-Pearce, ductal,Ehrlich tumor, Krebs 2, merkel cell, mucinous, non-small cell lung, oatcell, papillary, scirrhous, bronchiolar, bronchogenic, squamous cell,and transitional cell). Additional types of cancers that may be treatedinclude histiocytic disorders; leukemia; histiocytosis malignant;Hodgkin's disease; immunoproliferative small; non-Hodgkin's lymphoma;diffuse large B cell lymphoma, T-cell lymphoma, B-cell lymphoma, hairycell lymphoma, Burkitts lymphoma, plasmacytoma; reticuloendotheliosis;melanoma; chondroblastoma; chondroma; chondrosarcoma; fibroma;fibrosarcoma; giant cell tumors; histiocytoma; lipoma; liposarcoma;mesothelioma; myxoma; myxosarcoma; osteoma; osteosarcoma; chordoma;craniopharyngioma; dysgerminoma; hamartoma; mesenchymoma; mesonephroma;myosarcoma; ameloblastoma; cementoma; odontoma; teratoma; thymoma;trophoblastic tumor.

Other cancers that can be treated using the inventive compounds includewithout limitation adenoma; cholangioma; cholesteatoma; cyclindroma;cystadenocarcinoma; cystadenoma; granulosa cell tumor; gynandroblastoma;hepatoma; hidradenoma; islet cell tumor; Leydig cell tumor; papilloma;sertoli cell tumor; theca cell tumor; leimyoma; leiomyosarcoma;myoblastoma; myomma; myosarcoma; rhabdomyoma; rhabdomyosarcoma;ependymoma; ganglioneuroma; glioma; medulloblastoma; meningioma;neurilemmoma; neuroblastoma; neuroepithelioma; neurofibroma; neuroma;paraganglioma; paraganglioma nonchromaffin.

In one embodiment the inventive compounds are candidate therapeuticagents for the treatment of cancers such as angiokeratoma; angiolymphoidhyperplasia with eosinophilia; angioma sclerosing; angiomatosis;glomangioma; hemangioendothelioma; hemangioma; hemangiopericytoma;hemangiosarcoma; lymphangioma; lymphangiomyoma; lymphangiosarcoma;pinealoma; carcinosarcoma; chondrosarcoma; cystosarcoma phyllodes;fibrosarcoma; hemangiosarcoma; leiomyosarcoma; leukosarcoma;liposarcoma; lymphangiosarcoma; myosarcoma; myxosarcoma; ovariancarcinoma; rhabdomyosarcoma; sarcoma; neoplasms; nerofibromatosis; andcervical dysplasia.

In a particular embodiment, the present disclosure provides methods fortreating solid tumor, colon cancer, rectal cancer, colorectalcancer,bladder cancer, gastric cancer, esophageal cancer, head and neck cancer,myelodysplastic syndrome, brain cancer, CNS cancer, malignant glioma,glioblastoma, hepatocellular cancers, hepatocellular carcinoma, thyroidcancer, lung cancer, non-small cell lung cancer, a hematological cancer,leukemia, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, diffuselarge B cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, Burkittlymphoma, pancreatic cancer, melanoma, myeloma, multiple myeloma,pancreatic carcinoma, renal cell carcinoma, renal cancer, cervicalcancer, urothelial cancer, prostate cancer, castration-resistantprostate cancer, ovarian cancer, breast cancer or triple-negative breastcancer. According to such a method, a therapeutically effective amountof at least one compound according to Formula I or a stereoisomer,tautomer or pharmaceutically acceptable salt thereof can be administeredto a subject who has been diagnosed with a cell proliferative disease,such as a cancer. Alternatively, a pharmaceutical composition comprisingat least one compound according to Formula I or a stereoisomer, tautomeror pharmaceutically acceptable salt thereof can be administered to asubject who has been diagnosed with cancer.

In certain embodiments, the compounds in accordance with the inventionare administered to a subject with cancer in conjunction with otherconventional cancer therapies such as radiation treatment or surgery.Radiation therapy is well-known in the art and includes X-ray therapies,such as gamma-irradiation, and radiopharmaceutical therapies.

In certain embodiments, the inventive Mnk inhibitor compounds are usedwith at least one anti-cancer agent. Anti-cancer agents includechemotherapeutic drugs. A chemotherapeutic agent includes, but is notlimited to, an inhibitor of chromatin function, a topoisomeraseinhibitor, a microtubule inhibiting drug, a DNA damaging agent, anantimetabolite (such as folate antagonists, pyrimidine analogs, purineanalogs, and sugar-modified analogs), a DNA synthesis inhibitor, a DNAinteractive agent (such as an intercalating agent), and a DNA repairinhibitor.

Illustrative chemotherapeutic agents include, without limitation, thefollowing groups: anti-metabolites/anti-cancer agents, such aspyrimidine analogs (5-fluorouracil, floxuridine, capecitabine,gemcitabine and cytarabine) and purine analogs, folate antagonists andrelated inhibitors (mercaptopurine, thioguanine, pentostatin and2-chlorodeoxyadenosine (cladribine)); antiproliferative/antimitoticagents including natural products such as vinca alkaloids (vinblastine,vincristine, and vinorelbine), microtubule disruptors such as taxane(paclitaxel, docetaxel), vincristin, vinblastin, nocodazole, epothilonesand navelbine, epidipodophyllotoxins (etoposide, teniposide), DNAdamaging agents (actinomycin, amsacrine, anthracyclines, bleomycin,busulfan, camptothecin, carboplatin, chlorambucil, cisplatin,cyclophosphamide, Cytoxan, dactinomycin, daunorubicin, doxorubicin,epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan,merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,procarbazine, taxol, taxotere, temozolamide, teniposide,triethylenethiophosphoramide and etoposide (VP 16)); antibiotics such asdactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin),idarubicin, anthracyclines, mitoxantrone, bleomycins, plicamycin(mithramycin) and mitomycin; enzymes (L-asparaginase which systemicallymetabolizes L-asparagine and deprives cells which do not have thecapacity to synthesize their own asparagine); antiplatelet agents;antiproliferative/antimitotic alkylating agents such as nitrogenmustards (mechlorethamine, cyclophosphamide and analogs, melphalan,chlorambucil), ethylenimines and methylmelamines (hexamethylmelamine andthiotepa), alkyl sulfonates-busulfan, nitrosoureas (carmustine (BCNU)and analogs, streptozocin), trazenes—dacarbazinine (DTIC);antiproliferative/antimitotic antimetabolites such as folic acid analogs(methotrexate); platinum coordination complexes (cisplatin,carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide;hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide,nilutamide) and aromatase inhibitors (letrozole, anastrozole);anticoagulants (heparin, synthetic heparin salts and other inhibitors ofthrombin); fibrinolytic agents (such as tissue plasminogen activator,streptokinase and urokinase), aspirin, dipyridamole, ticlopidine,clopidogrel, abciximab; antimigratory agents; antisecretory agents(breveldin); immunosuppressives (cyclosporine, tacrolimus (FK-506),sirolimus (rapamycin), azathioprine, mycophenolate mofetil);anti-angiogenic compounds (TNP470, genistein) and growth factorinhibitors (vascular endothelial growth factor (VEGF) inhibitors,fibroblast growth factor (FGF) inhibitors); angiotensin receptorblocker; nitric oxide donors; anti-sense oligonucleotides; antibodies(trastuzumab, rituximab); chimeric antigen receptors; cell cycleinhibitors and differentiation inducers (tretinoin); mTOR inhibitors,topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine,camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin,etoposide, idarubicin, irinotecan (CPT-11) and mitoxantrone, topotecan,irinotecan), corticosteroids (cortisone, dexamethasone, hydrocortisone,methylpednisolone, prednisone, and prenisolone); growth factor signaltransduction kinase inhibitors; mitochondrial dysfunction inducers,toxins such as Cholera toxin, ricin, Pseudomonas exotoxin, Bordetellapertussis adenylate cyclase toxin, or diphtheria toxin, and caspaseactivators; and chromatin disruptors.

In certain embodiments, an Mnk inhibitor in accordance with the presentinvention is used simultaneously, in the same formulation or in separateformulations, or sequentially with an additional agent(s) as part of acombination therapy regimen.

Mnk inhibitors according to Formula I, Ia, IIa, IIb, IIIa, IIIb, IVa,IVb, Va, Vb, VI, VIIa, and VIIb including their corresponding salts andpharmaceutical compositions of Formula I, Ia, IIa, IIb, IIIa, IIIb, IVa,IVb, Va, Vb, VI, VIIa, and VIIb compounds are also effective astherapeutic agents for treating or preventing cytokine mediateddisorders, such as inflammation in a patient, preferably in a human. Inone embodiment, a compound or composition in accordance with theinvention is particularly useful for treating or preventing a diseaseselected from the group consisting of chronic or acute inflammation,chronic inflammatory arthritis, rheumatoid arthritis, psoriasis, COPD,inflammatory bowel disease, septic shock, Crohn's disease, ulcerativecolitis, multiple sclerosis and asthma.

In a further aspect of the invention, the inventive compounds orpharmaceutically acceptable formulations of the inventive compounds areprovided as inhibitors of Mnk activity. Such inhibition is achieved bycontacting a cell expressing Mnk with a compound or a pharmaceuticallyacceptable formulation, to lower or inhibit Mnk activity, to providetherapeutic efficacy for a Mnk dependent condition in a mammal in needthereof.

Therapeutically effective dosages of a compound according to Formula Ior a composition of a Formula I compound will generally range from about1 to 2000 mg/day, from about 10 to about 1000 mg/day, from about 10 toabout 500 mg/day, from about 10 to about 250 mg/day, from about 10 toabout 100 mg/day, or from about 10 to about 50 mg/day. Thetherapeutically effective dosages may be administered in one or multipledoses. It will be appreciated, however, that specific doses of thecompounds of the invention for any particular patient will depend on avariety of factors such as age, sex, body weight, general healthcondition, diet, individual response of the patient to be treated, timeof administration, severity of the disease to be treated, the activityof particular compound applied, dosage form, mode of application andconcomitant medication. The therapeutically effective amount for a givensituation will readily be determined by routine experimentation and iswithin the skills and judgment of the ordinary clinician or physician.In any case the compound or composition will be administered at dosagesand in a manner which allows a therapeutically effective amount to bedelivered based upon patient's unique condition.

Synthesis

The following examples are provided for purpose of illustration and notlimitation.

Example 1 Synthesis of7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione(Cpd. No. 1)

Synthesis of7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H)-dione(3)

To a solution of 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxylic acid(1, 0.25 g, 1.44 mmol) in acetonitrile (10 mL),2-((4-methoxybenzyl)amino)ethanol (2, 0.31 g, 1.73 mmol) followed bycesium carbonate (1.18 g, 3.61 mmol) and HATU (1.26 g, 3.32 mmol) wereadded and the reaction mixture was stirred at 50° C. for 16 h. Thereaction mixture was diluted with water and the compound was extractedin ethyl acetate. The organic layer was washed with brine, separated,dried over sodium sulphate and concentrated under reduced pressure. Theresidue obtained was purified via column chromatography (silica, ethylacetate/hexanes=60%) to afford7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H)-dione(3). Yield: 0.24 g, 52%; MS (ESI) m/z 319 [M+1]⁺.

Synthesis of2-(4-methoxybenzyl)-7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione(5)

To a solution of7-chloro-2-(4-methoxybenzyl)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6-(2H)-dione(3, 0.45 g, 1.41 mmol) in dioxane (10 mL), pyrimidin-4-amine (4, 0.13 g,1.41 mmol), sodium tert-butoxide (0.41 g, 4.2 mmol) followed by X-Phos(0.14 g, 0.28 mmol) were added and the reaction mixture was degassedwith argon for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (0.13 g,0.14 mmol) was added and the reaction mixture was degassed with argonfor another 5 min and stirred at 110° C. for 16 h. The reaction mixturewas diluted with water and the compound was extracted in ethyl acetate.The organic layer was washed with brine, separated, dried over sodiumsulphate and concentrated under reduced pressure. The residue obtainedwas purified via column chromatography (silica,methanol/dichloromethane=5%) to afford2-(4-methoxybenzyl)-7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione(5) as a yellow solid. Yield: 0.42 g, 79%; MS (ESI) m/z 378 [M+1]⁺.

Synthesis of7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione(Cpd. No. 1)

A solution of2-(4-methoxybenzyl)-7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione(5, 0.3 g, 0.79 mmol) in trifluoroacetic acid (5 mL) was heated at 90°C. for 48 h. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The residue was neutralized withsaturated solution of sodium bicarbonate and the compound was extractedin 10% methanol in ethyl acetate. The organic layer was separated, driedover sodium sulphate, concentrated under reduced pressure and theresidue obtained was purified via column chromatography (silica,methanol/dichloromethane=10%) to afford7-(pyrimidin-4-ylamino)-3,4-dihydro-1H-pyrido[1,2-a]pyrazine-1,6(2H)-dione(Cpd. No. 1) as a beige solid. Yield: 0.12 g, 59%; MS (ESI) m/z 258[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.79-8.64 (m, 2H),8.48 (s, 1H), 8.38 (d, J=5.9 Hz, 1H), 7.41 (dd, J=6.0, 1.3 Hz, 1H), 7.11(d, J=7.9 Hz, 1H), 4.23-4.16 (m, 2H), 3.55-3.48 (m, 2H).

Example 2 Synthesis of3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 2)

Synthesis of 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2)

Aqueous ammonia (15 mL, 30% solution) was added to ethyl5-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (1, 0.65 g, 3.2 mmol)at 0° C. and the reaction mixture was allowed to stir at roomtemperature for 16 h. The reaction mixture was concentrated underreduced pressure and the residue was triturated with diethyl ether,filtered and dried to afford5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2). Yield: 0.43 g,75%; MS (ESI) m/z 173[M+1]⁺.

Synthesis of6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (4)

Procedure A: To a solution of5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (2, 1.4 g, 7.9 mmol) in1,4-dioxane (20 mL), acetone (3, 4.6 g, 79 mmol) and concentratedsulfuric acid (0.038 g, 0.39 mmol) were added at room temperature andthe reaction mixture was allowed to heat at 100° C. for 8 h. Thereaction mixture was concentrated under reduced pressure and the residuewas triturated with diethyl ether and hexane, filtered and dried toafford 6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(4). Yield: 1.4 g, 83%; MS (ESI) m/z 213[M+1]⁺.

Synthesis of3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 2)

Procedure B: To a solution of6-chloro-3,3-dimethyl-2,3-dihydroimidazo[1,5-c]pyridine-1,5-dione (4,0.25 g, 1.18 mmol) in 1,4-dioxane (8 mL), pyrimidin-4-amine (5, 0.14 g,1.41 mmol), Brettphos (0.19 g, 0.23 mmol) and cesium carbonate (0.76 g,2.36 mmol) were added and the reaction mixture was degassed with argonfor 5 min. Tris dibenzylideneacetone dipalladium (0) (0.11 g, 0.12 mmol)was added. The reaction was degassed with argon for another 5 min andthen stirred at 100° C. for 10 h. The reaction mixture was cooled toroom temperature, filtered through celite and the filtrate wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography using 5% methanol in dichloromethane to afford3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 2) as a light yellow solid. Yield: 0.036 g, 11%; MS (ESI) m/z272[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 9.42 (s, 1H),8.81-8.73 (m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.87 (d,J=7.7 Hz, 1H), 1.82 (s, 6H).

Example 3 Synthesis of3-(4-fluorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 3)

Synthesis of6-chloro-3-(4-fluorobenzyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.17 g, 49%; MS (ESI) m/z307[M+1]⁺.

Synthesis of3-(4-fluorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 3)

The synthesis of compound 3 was carried out as described above using thegeneral protocol of Procedure B. White solid; Yield: 0.012 g, 40%; MS(ESI) m/z 366[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H), 9.50 (s,1H), 8.75 (s, 1H), 8.68 (d, J=7.6 Hz, 1H), 8.40 (d, J=5.9 Hz, 1H), 7.41(d, J=5.9 Hz, 1H), 7.04-6.92 (m, 4H), 6.57 (d, J=7.7 Hz, 1H), 3.99 (d,J=13.9 Hz, 1H), 3.07 (d, J=13.9 Hz, 1H), 1.97 (s, 3H).

Example 4 Synthesis of3-(4-chlorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 4)

Synthesis of6-chloro-3-(4-chlorobenzyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.278 g, 59%; MS (ESI) m/z323 [M+1]⁺.

Synthesis of3-(4-chlorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 4)

The synthesis of compound 4 was carried out as described above using thegeneral protocol of Procedure B. Tan solid; Yield: 0.18 g, 59%; MS (ESI)m/z 382[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 1H), 9.51 (s, 1H),8.75 (s, 1H), 8.68 (d, J=7.6 Hz, 1H), 8.40 (d, J=5.9 Hz, 1H), 7.41 (d,J=6.1 Hz, 1H), 7.20-7.01 (m, 1H), 6.99-6.92 (m, 2H), 6.77 (dd, J=8.6,5.0 Hz, 1H), 6.58 (d, J=7.6 Hz, 1H), 4.02 (d, J=13.8 Hz, 1H), 3.12 (d,J=13.8 Hz, 1H), 1.98 (s, 3H).

Example 5 Synthesis of3-(3-fluorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 5)

Synthesis of6-chloro-3-(3-fluorobenzyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.265 g, 59%; MS (ESI) m/z307 [M+1]⁺.

Synthesis of3-(3-fluorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 5)

The synthesis of compound 5 was carried out as described above using thegeneral protocol of Procedure B. Beige solid; Yield: 0.17 g, 56%; MS(ESI) m/z 366[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 1H), 9.51 (s,1H), 8.75 (s, 1H), 8.68 (d, J=7.6 Hz, 1H), 8.40 (d, J=5.9 Hz, 1H), 7.41(d, J=6.1 Hz, 1H), 7.2-7.08 (m, 1H), 6.99-6.91 (m, 1H), 6.77 (dd, J=8.6,5.0 Hz, 2H), 6.58 (d, J=7.6 Hz, 1H), 4.02 (d, J=13.8 Hz, 1H), 3.12 (d,J=13.8 Hz, 1H), 1.98 (s, 3H).

Example 6 Synthesis of6′-(pyrimidin-4-ylamino)-1H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridine]-1′,5′(2′H)-dione(Cpd. No. 6)

Synthesis of6′-chloro-1′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridine]-1′,5′(2′H)-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.18 g, 42%; MS (ESI) m/z239[M+1]⁺.

Synthesis of6′-(pyrimidin-4-ylamino)-1′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]-pyridine]-1′,5′(2′H)-dione(Cpd. No. 6)

The synthesis of compound 6 was carried out as described above using thegeneral protocol of Procedure B. Light brown solid; Yield: 0.1 g, 45%;MS (ESI) m/z 298.10[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.01 (s, 1H),9.43 (s, 1H), 8.82-8.73 (m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.37 (d, J=5.9Hz, 1H), 6.88 (d, J=7.6 Hz, 1H), 2.89-2.81 (m, 2H), 2.08-1.92 (m, 2H),1.96-1.70 (m, 4H).

Example 7 Synthesis of3-methyl-6-(pyrimidin-4-ylamino)-3-(2,2,2-trifluoroethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 7)

Synthesis of6-chloro-3-methyl-3-(2,2,2-trifluoroethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.12 g, 22%.

Synthesis of3-methyl-6-(pyrimidin-4-ylamino)-3-(2,2,2-trifluoroethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 7)

The synthesis of compound 7 was carried out as described above using thegeneral protocol of Procedure B. Green-yellow solid; Yield: 0.020 g,15%; MS (ESI) m/z 340[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s, 1H),9.42 (s, 1H), 8.70 (dd, J=4.5, 1.7 Hz, 1H), 8.79 (s, 1H), 8.30-8.20 (m,1H), 7.73 (d, J=1.1 Hz, 1H), 7.32 (dd, J=9.2, 4.4 Hz, 1H), 3.38-3.75 (m,1H), 3.19-3.08 (m, 1H), 1.81 (s, 3H).

Example 8 Synthesis of3-isopropyl-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 8)

Synthesis of6-chloro-3-isopropyl-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.32 g, 77%.

Synthesis of3-isopropyl-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 8)

The synthesis of compound 8 was carried out as described above using thegeneral protocol of Procedure B. Off-white solid; Yield: 0.036 g, 19%;MS (ESI) m/z 300[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, 1H), 9.41(s, 1H), 8.83-8.73 (m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.37 (d, J=5.9 Hz,1H), 6.87 (d, J=7.6 Hz, 1H), 3.1-2.90 (m, 1H), 1.83 (s, 3H), 1.05 (d,J=7.0 Hz, 3H), 0.46 (d, J=6.6 Hz, 3H).

Example 9 Synthesis of3-cyclopentyl-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 9)

Synthesis of6-chloro-3-cyclopentyl-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.2 g, 47%; MS (ESI) m/z267[M+1]⁺.

Synthesis of3-cyclopentyl-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 9)

The synthesis of compound 9 was carried out as described above using thegeneral protocol of Procedure B. Beige solid; Yield: 0.12 g, 47%; MS(ESI) m/z 326[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 9.39 (s,1H), 8.81-8.73 (m, 2H), 8.37 (d, J=5.9 Hz, 1H), 7.39-7.32 (m, 1H), 6.86(d, J=7.7 Hz, 1H), 3.45-3.40 (m, 1H), 1.84 (s, 3H), 1.68-1.35 (m, 4H),1.18-1.1 (m, 1H), 0.85-0.80 (m, 1H).

Example 10 Synthesis ofN-(6-((3,3-dimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 10)

Synthesis ofN-(6-((3,3-dimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)-amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 10)

The synthesis of compound 10 was carried out as described above usingthe general protocol of Procedure B. Beige solid; Yield: 0.075 g, 15%;MS (ESI) m/z 355[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s, 1H), 9.68(s, 1H), 9.20 (s, 1H), 8.64 (d, J=7.7 Hz, 1H), 8.51 (s, 1H), 7.88 (d,J=1.0 Hz, 1H), 6.85 (d, J=7.6 Hz, 1H), 2.02 (m, J=6.2 Hz, 1H), 1.80 (s,6H), 0.84 (d, J=6.1 Hz, 4H).

Example 11 Synthesis of3-(4-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 11)

Synthesis of6-chloro-3-(4-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.216 g, 52%; MS (ESI) m/z293 [M+1]⁺.

Synthesis of3-(4-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 11)

The synthesis of compound 11 was carried out as described above usingthe general protocol of Procedure B. Brown solid; Yield: 0.14 g, 41%; MS(ESI) m/z 252.15 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, 1H), 9.35(s, 1H), 8.83-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.44 (dd, J=8.5, 5.2Hz, 2H), 7.31-7.16 (m, 3H), 6.99 (d, J=7.6 Hz, 1H), 2.26 (s, 3H).

Example 12 Synthesis of3-(3-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 12)

Synthesis of6-chloro-3-(3-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.208 g, 50%; MS (ESI) m/z293 [M+1]⁺.

Synthesis of3-(3-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 12)

The synthesis of compound 12 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.08 g, 34%;MS (ESI) m/z 252.25 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s, 1H),9.34 (s, 1H), 8.84-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.43 (m, 1H),7.32-7.12 (m, 4H), 7.00 (d, J=7.6 Hz, 1H), 2.26 (s, 3H).

Example 13 Synthesis of3-(4-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 13)

Synthesis of6-chloro-3-(4-chlorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.17 g, 31%; MS (ESI) m/z309 [M+1]⁺.

Synthesis of3-(4-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 13)

The synthesis of compound 13 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.11 g, 55%;MS (ESI) m/z 368.15 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, 1H),9.32 (s, 1H), 8.84-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.42 (m, 4H),7.27 (dd, J=5.9, 1.3 Hz, 1H), 7.00 (d, J=7.7 Hz, 1H), 2.25 (s, 3H).

Example 14 Synthesis of3-methyl-6-(pyrimidin-4-ylamino)-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 14)

Synthesis of6-chloro-3-methyl-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.255 g, 66%; MS (ESI) m/z267 [M+1]⁺

Synthesis of3-methyl-6-(pyrimidin-4-ylamino)-3-(trifluoromethyl)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 14)

The synthesis of compound 14 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 0.06 g,19%; MS (ESI) m/z 326 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H),9.58 (s, 1H), 8.84-8.76 (m, 2H), 8.41 (d, J=5.9 Hz, 1H), 7.40 (dd,J=5.9, 1.4 Hz, 1H), 7.02 (d, J=7.7 Hz, 1H), 2.14 (s, 3H).

Example 15 Synthesis of3-(aminomethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 15)

Synthesis of6-chloro-3-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.5 g, 50%; MS (ESI) m/z 358[M+1]⁺.

Synthesis of3-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Yield: 0.09 g, 26%; MS (ESI) m/z417[M+1]⁺.

Synthesis of3-(aminomethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 15)

Procedure C: To a solution of3-((1,3-dioxoisoindolin-2-yl)methyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(5, 0.085 g, 0.29 mmol) in methanol (20 mL), hydrazine hydrate (2 mL)was added and the reaction mixture was stirred at room temperature for16 h. The reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The residue was dissolved indichloromethane and washed with water, separated, dried over sodiumsulphate and concentrated under reduced pressure, which was purified byrepeated washing with diethyl ether and hexane to obtain3-(aminomethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 15) as an off-white solid. Yield: 0.008 g, 9%; MS (ESI) m/z287.05[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 8.76 (d, J=7.8Hz, 2H), 8.36 (d, J=5.9 Hz, 1H), 7.36 (d, J=6.0 Hz, 1H), 6.83 (d, J=7.6Hz, 1H), 3.55 (d, J=13.6 Hz, 1H), 2.92 (d, J=13.7 Hz, 1H), 1.75 (s, 3H),1.44 (s, 1H), 1.41-1.34 (m, 2H).

Example 16 Synthesis of3-methyl-6-(pyrimidin-4-ylamino)-3-(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 16)

Synthesis of6-chloro-3-methyl-3-(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

To a solution of 5-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide (1,0.1 g, 0.58 mmol) in acetonitrile (4 mL), 1-(thiophen-3-yl)ethanone (2,0.37 g, 2.9 mmol) and ferric chloride (0.094 g, 0.58 mmol) were addedand the reaction mixture was allowed to heat at 90° C. for 18 h. Thereaction mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was purified by column chromatography(silica, ethyl acetate/hexanes=50%) to afford6-chloro-3-methyl-3-(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3). Yield: 0.021 g, 13%; MS (ESI) m/z 281[M+1]⁺.

Synthesis of3-methyl-6-(pyrimidin-4-ylamino)-3-(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 16)

The synthesis of compound 16 was carried out as described above usingthe general protocol of Procedure B. Beige solid; Yield: 0.008 g, 12%;MS (ESI) m/z 340[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, 1H), 9.35(s, 1H), 8.81-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.74-7.68 (m, 1H),7.49 (dd, J=5.1, 2.9 Hz, 1H), 7.29 (d, J=5.9 Hz, 1H), 7.00-6.92 (m, 2H),2.25 (s, 3H).

Example 17 Synthesis of3-methyl-6-(pyrimidin-4-ylamino)-3-(thiazol-4-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 17)

Synthesis of6-chloro-3-methyl-3-(thiazol-4-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.2 g, 49%; MS (ESI) m/z282[M+1]⁺.

Synthesis of3-methyl-6-(pyrimidin-4-ylamino)-3-(thiazol-4-yl)-2,3-dihydroimidazo[1,5-a]-pyridine-1,5-dione(Cpd. No. 17)

The synthesis of compound 17 was carried out as described above usingthe general protocol of Procedure B. Yellow solid. Yield: 0.013 g, 21%;MS (ESI) m/z 341[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.97 (s, 1H), 9.43(s, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.83-8.71 (m, 2H), 8.35 (d, J=6.0 Hz,1H), 8.07 (d, J=1.9 Hz, 1H), 7.27 (d, J=6.0 Hz, 1H), 6.94 (d, J=7.6 Hz,1H), 2.30 (s, 3H).

Example 18 Synthesis of3-(3-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 18)

Synthesis of6-chloro-3-(3-chlorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.210 g, 39%; MS (ESI) m/z309 [M+1]⁺.

Synthesis of3-(3-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 18)

The synthesis of compound 18 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.053 g,22%; MS (ESI) m/z 368 [M+1]+; ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s, 1H),9.35 (s, 1H), 8.86-8.73 (m, 2H), 8.35 (d, J=5.9 Hz, 1H), 7.51-7.34 (m,3H), 7.34-7.23 (m, 2H), 7.09 (s, 1H), 7.01 (d, J=7.6 Hz, 1H), 2.25 (s,3H).

Example 19 Synthesis of3-(3-chlorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 19)

Synthesis of6-chloro-3-(3-chlorobenzyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.4 g, 70%; MS (ESI) m/z 324[M+1]⁺

Synthesis of3-(3-chlorobenzyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 19)

The synthesis of compound 19 was carried out as described above usingthe general protocol of Procedure B. White solid; Yield: 0.2 g, 56%; MS(ESI) m/z 382 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, 1H), 9.49 (s,1H), 8.75 (s, 1H), 8.68 (d, J=7.7 Hz, 1H), 8.39 (d, J=5.9 Hz, 1H), 7.41(d, J=5.9 Hz, 1H), 7.24-7.12 (m, 2H), 7.04 (d, J=2.3 Hz, 1H), 6.87 (dd,J=6.8, 2.1 Hz, 1H), 6.58 (d, J=7.7 Hz, 1H), 4.00 (d, J=13.8 Hz, 1H),3.11 (d, J=13.8 Hz, 1H), 1.97 (s, 3H).

Example 20 Synthesis of 6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5(2H)-dione (Cpd. No. 20)

Synthesis of6-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.504 g, crude; MS (ESI) m/z254 [M+1]⁺.

Synthesis of tert-butyl6-chloro-1,5-dioxo-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate(4)

To a solution of1′-benzyl-6-chloro-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5(2H)-dione(3, 0.5 g, 1.9 mmol) in tetrahydrofuran (8 mL) and water (4 mL), sodiumbicarbonate (0.66 g, 7.8 mmol) and di-tertiarybutyl dicarbonate (1.31mL, 5.9 mmol) were added at 0° C. and the reaction mixture was allowedto stir at room temperature for 2 h. The reaction mixture was dilutedwith water and the compound was extracted in ethyl acetate. The organiclayer was separated, dried over sodium sulphate and concentrated underreduced pressure. The residue was purified by column chromatography(silica, methanol/dichloromethane=2%) to afford tert-butyl6-chloro-1,5-dioxo-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate4. Yield: 0.33 g, 47%; MS (ESI) m/z 354 [M+1]⁺.

Synthesis of tert-butyl1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate(6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure B. Yield: 0.126 g, 31%; MS (ESI) m/z413 [M+1]⁺.

Synthesis of6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5(2H)-dione(Cpd. No. 20)

Procedure D: To a stirred solution of1′-benzyl-6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5(2H)-dione(5, 0.12 g, 0.29 mmol) in dioxane (1 mL), 4 M hydrogenchloride indioxane (2 mL) was added at 0° C. and the reaction mixture was stirredat room temperature for 3 h. The solvent was removed under reducedpressure and the residue was purified by repeated washing with pentane.Compound was dissolved in water and passed through strata column toobtain6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5(2H)-dione(Cpd. No. 20) as a light brown solid. Yield: 0.062 g, 67%; MS (ESI) m/z313.15 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.13 (s, 1H), 9.40 (s, 1H),8.80-8.73 (m, 2H), 8.38 (d, J=5.9 Hz, 1H), 7.37 (dd, J=5.9, 1.3 Hz, 1H),6.89 (d, J=7.7 Hz, 1H), 3.94 (d, J=12.5 Hz, 1H), 3.16-3.12 (m, 1H), 2.95(d, J=13.1 Hz, 1H), 2.74-2.65 (m, 1H), 2.60 (s, 1H), 2.46 (d, J=11.7 Hz,1H), 1.72 (d, J=8.2 Hz, 2H), 1.61 (d, J=13.0 Hz, 1H).

Example 21 Synthesis ofN-[6-[(1,5-dioxospiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 21)

Synthesis of6-chlorospiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 0.8 g, 58%;MS (ESI) m/z 237 [M−1]⁻; ¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H), 7.94(m, 1H), 6.72 (m, 1H), 2.76 (m, 2H), 1.95 (m, 2H), 1.82 (m, 2H), 1.70(m, 2H).

Synthesis ofN-[6[(1,5-dioxospiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 21)

The synthesis of compound 21 was carried out as described above usingthe general protocol of Procedure B. Off white solid; Yield: 0.12 g,15%; MS (ESI) m/z 381.13 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s,1H), 10.01 (s, 1H), 9.24 (s, 1H), 8.65 (d, J=7.6 Hz, 1H), 8.50 (s, 1H),7.87 (s, 1H), 6.85 (d, J=7.6 Hz, 1H), 2.80 (m, 2H), 2.01 (m, 3H), 1.86(s, 2H), 1.72 (m, 2H), 0.83 (m, 4H).

Example 22 Synthesis ofN-(6-((3-methyl-1,5-dioxo-3-(2,2,2-trifluoroethyl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 22)

Synthesis of6-chloro-3-methyl-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 0.35 g, 43%; MS(ESI) m/z 279.1 [M−1]⁻; ¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (bs, 1H), 7.99(d, J=4 Hz, 1H), 6.79 (d, J=4 Hz, 1H), 3.74-3.65 (m, 1H), 3.17-3.01 (m,1H), 1.84 (s, 3H).

Synthesis ofN-[6-[[3-methyl-1,5-dioxo-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 22)

The synthesis of compound 22 was carried out as described above usingthe general protocol of Procedure B. Brown solid; Yield: 0.2 g, 28%; MS(ESI) m/z 423.1[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H), 9.80(s, 1H), 9.29 (s, 1H), 8.69 (d, J=7.6 Hz, 1H), 8.51 (s, 1H), 7.90 (s,1H), 6.93 (d, J=7.6 Hz, 1H), 3.82-3.70 (m, 1H), 3.16-3.04 (m, 1H),2.07-1.99 (m, 1H), 1.80 (s, 3H), 0.84 (d, J=6.0 Hz, 4H).

Example 23 Synthesis ofN-[6-[(3-cyclopentyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 23)

Synthesis of6-chloro-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 1.61 g,52%; MS (ESI) m/z 267.0 [M+1]⁺; ¹H NMR (400 MHz, CDCl₃) δ 8.61 (s, 1H),7.71 (d, J=7.2 Hz, 1H), 6.77 (d, J=7.2 Hz, 1H), 3.54 (m, 1H), 2.01 (m,1H), 1.98 (s, 3H), 1.68 (m, 2H), 1.55 (m, 2H), 1.34 (m, 2H), 0.91 (m,1H).

Synthesis ofN-[6[(3-cyclopentyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)-amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 23)

The synthesis of compound 23 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 1.4 g, 57%;MS (ESI) m/z 409.36 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H),9.69 (s, 1H), 9.17 (s, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.50 (s, 1H), 7.85(s, 1H), 6.83 (d, J=7.6 Hz, 1H), 3.39 (m, 1H), 2.02 (m, 1H), 1.83 (s,3H), 1.82 (m, 1H), 1.51 (m, 5H), 1.10 (m, 1H), 0.83 (d, J=6.0 Hz, 4H),0.78 (m, 1H).

Example 24 Synthesis ofN-[6-[[3-methyl-1,5-dioxo-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 24)

Synthesis of6-chloro-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 6.50 g,84%; MS (ESI) m/z 267.11 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s,1H), 8.10 (d, J=7.2 Hz, 1H), 6.85 (d, J=7.2 Hz, 1H), 2.09 (s, 3H).

Synthesis ofN-[6-[[3-methyl-1,5-dioxo-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 24)

The synthesis of compound 24 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 1.75 g,64%; MS (ESI) m/z 409.29 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s,1H), 10.48 (s, 1H), 9.43 (s, 1H), 8.68 (d, J=7.6 Hz, 1H), 8.53 (s, 1H),7.94 (s, 1H), 6.97 (d, J=8.0 Hz, 1H), 2.17 (s, 3H), 2.02 (m, 1H), 0.84(d, J=6.0 Hz, 4H).

Example 25 Synthesis of3-methyl-3-((methylamino)methyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 25)

Synthesis of6-chloro-3-methyl-3-((methylamino)methyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.56 g, crude; MS (ESI) m/z242 [M+1]⁺.

Synthesis of tert-butyl((6-chloro-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-3-yl)methyl)(methyl)carbamate(4)

To a stirred solution of6-chloro-3-methyl-3-((methylamino)methyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3, 0.56 g, 2.3 mmol) in tetrahydrofuran (2 mL), sodium bicarbonate(2.91 g, 34.0 mmol) followed by di-tertiary butyl dicarbonate (2.58 mL,11.0 mmol) were added and the reaction mixture was heated at 100° C. for16 h. The reaction mixture was quenched with water and the compound wasextracted in ethyl acetate. The organic layer was washed with 0.5 Mhydrochloric acid and brine, separated, dried over sodium sulphate andconcentrated under reduced pressure, and the residue was purified byrepeated washing with pentane to obtain tert-butyl((6-chloro-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-c]pyridin-3-yl)methyl)(methyl)carbamate(4). Yield: 0.67 g, crude; MS (ESI) m/z 343[M+1]⁺.

Synthesis of tert-butylmethyl((3-methyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-3-yl)methyl)carbamate(6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure B. Yield: 0.340 g, 72%; MS (ESI) m/z401 [M+1]⁺.

Synthesis of3-methyl-3-((methylamino)methyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 25)

The synthesis of compound 25 was carried out as described above usingthe general protocol of Procedure D. Light yellow solid; Yield: 0.11 g,44%; MS (ESI) m/z 301.20 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s,2H), 8.75 (d, J=6.8 Hz, 2H), 8.36 (d, J=5.8 Hz, 1H), 7.36 (d, J=5.9 Hz,1H), 6.82 (d, J=7.1 Hz, 1H), 3.58 (d, J=13.1 Hz, 1H), 2.82 (d, J=13.1Hz, 1H), 2.16 (s, 3H), 1.76 (s, 3H).

Example 26 Synthesis of6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1,5(2H)-dione(Cpd. No. 26)

Synthesis of benzyl6-chloro-1,5-dioxo-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1′-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.4 g, 37%; MS (ESI) m/z 374[M+1]⁺.

Synthesis of benzyl1,5-dioxo-6-(pyrimidin-4-ylamino)-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1′-carboxylate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Yield: 0.1 g, 34%; MS (ESI) m/z 432[M+1]⁺.

Synthesis of6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1,5(2H)-dione(Cpd. No. 26)

To a stirred solution of benzyl1,5-dioxo-6-(pyrimidin-4-ylamino)-2,5-dihydro-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1′-carboxylate(5, 0.06 g, 0.138 mmol) in ethyl acetate: methanol (10:1, 33 mL), 20%palladium hydroxide (0.03 g) was added. The reaction mixture washydrogenated under balloon pressure for 4 h. The progress of thereaction was monitored by TLC. After complete consumption of startingmaterial, the reaction mixture was filtered through a pad of celite andthe filtrate was concentrated under reduced pressure. The residue waspurified by preparative TLC and repeated washing with ether to afford6-(pyrimidin-4-ylamino)-1H-spiro[imidazo[1,5-a]pyridine-3,3′-pyrrolidine]-1,5(2H)-dione(Cpd. No. 26) as a white solid. Yield: 0.025 g, 60%; MS (ESI) m/z 299.20[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 8.83-8.74 (m, 2H),8.38 (d, J=5.9 Hz, 1H), 7.37 (d, J=5.9 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H),3.67 (d, J=12.6 Hz, 1H), 3.19-3.03 (m, 2H), 2.95-2.75 (m, 2H), 2.05-1.88(m, 1H).

Example 27 Synthesis of3-(3,5-difluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 27)

Synthesis of6-chloro-3-(3,5-difluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 0.21 g, 23%; MS(ESI) m/z 311 [M+1]⁺.

Synthesis of3-(3,5-difluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 27)

The synthesis of compound 27 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.12 g, 50%;MS (ESI) m/z 370 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 9.37(s, 1H), 8.85-8.74 (m, 2H), 8.36 (d, J=5.9 Hz, 1H), 7.33-7.23 (m, 2H),7.13 (d, J=8.0 Hz, 2H), 7.01 (d, J=7.7 Hz, 1H), 2.23 (s, 3H).

Example 28 Synthesis of3-(3-chloro-5-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 28)

Synthesis of6-chloro-3-(3-chloro-5-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.2 g, 21%; MS (ESI) m/z326[M+1]⁺.

Synthesis of3-(3-chloro-5-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 28)

The synthesis of compound 28 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.065 g, 27%;MS (ESI) m/z 286.25[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.10 (s, 1H),9.39 (s, 1H), 8.86-8.74 (m, 2H), 8.36 (d, J=5.8 Hz, 1H), 7.53-7.45 (m,1H), 7.33-7.24 (m, 3H), 7.22 (s, 1H), 2.23 (s, 3H).

Example 29 Synthesis ofN-[6-[(3-isopropyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 29)

Synthesis of6-chloro-3-isopropyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid. Yield: 0.80 g,82%; MS (ESI) m/z 241.08 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 9.94 (s,1H), 7.95 (d, J=8.0 Hz, 1H), 6.71 (m, 1H), 3.01 (m, 1H), 1.79 (s, 3H),1.03 (d, J=6.8 Hz, 3H), 0.42 (d, J=6.4 Hz, 3H).

Synthesis ofN-[6[(3-isopropyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)-amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 29)

The synthesis of compound 29 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 0.060 g,13%; MS (ESI) m/z 383.30 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s,1H), 9.65 (s, 1H), 9.20 (s, 1H), 8.66 (d, J=7.6 Hz, 1H), 8.51 (s, 1H),7.87 (s, 1H), 6.84 (d, J=7.6 Hz, 1H), 3.08 (m, 1H), 2.02 (m, 1H), 1.82(s, 3H), 1.04 (d, J=6.8 Hz, 3H), 0.83 (d, J=6.0 Hz, 4H), 0.46 (d, J=6.4Hz, 3H).

Example 30 Synthesis ofN-[6-[[3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 30)

Synthesis of6-chloro-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 300 mg, 59%; MS(ESI) m/z 293.13 [M+1]⁺.

Synthesis ofN-[6-[[3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 30)

The synthesis of compound 30 was carried out as described above usingthe general protocol of Procedure B. White solid; Yield: 100 mg, 22%; MS(ESI) m/z 435.28 [M+1]+; ¹H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H),10.03 (s, 1H), 9.17 (s, 1H), 8.69 (d, J=7.6 Hz, 1H), 8.50 (s, 1H), 7.81(s, 1H), 7.43 (m, 1H), 7.23 (m, 2H), 7.14 (m, 1H), 6.85 (d, J=7.6 Hz,1H), 2.24 (s, 3H), 2.01 (m, 1H), 0.82 (d, J=6.0 Hz, 4H).

Example 31 Synthesis of6-[[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 31)

Synthesis of tert-butylN-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3)

A mixture of [(E)-2-cyclopropylvinyl]boronic acid (1, 1.0 g, 8.93 mmol),tert-butyl N-tert-butoxycarbonyl-N-(6-chloropyrimidin-4-yl)carbamate (2,3.24 g, 9.83 mmol), sodium carbonate (2.84 g, 26.8 mmol), 1,4-dioxane(10 mL) and water (3 mL) in a microwave vial was degassed with argon for10 minutes. To this mixture1,1-bis(diphenylphosphino)ferrocene-palladium(II)dichloridedichloromethane complex (0.73 g, 0.89 mmol) was added and purged withargon for 5 minutes. After sealing, the vial was irradiated in amicrowave reactor at 130° C. for 45 minutes. The reaction mixture wasdiluted with water (20 mL) and extracted with ethyl acetate (3×30 mL).The organics were washed with water (2×10 mL) and saturated brinesolution (1×10 mL). The organics were then separated, dried with sodiumsulfate, and filtered before concentration to dryness. The crude residuewas purified by column chromatography (silica, ethylacetate/hexanes=25%) to obtain tert-butylN-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3) as a lightbrown solid. Yield: 370 mg, 16%; MS (ESI) m/z 262.22 [M+1-Boc]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 10.23 (s, 1H), 8.60 (s, 1H), 7.63 (s, 1H), 6.50 (m,2H), 1.48 (s, 9H), 0.91 (m, 2H), 0.64 (m, 2H)

Synthesis of 6-[(E)-2-cyclopropylvinyl]pyrimidin-4-amine (4)

A solution of tert-butylN-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3, 350 mg, 1.34mmol) in dichloromethane (10 mL) at 0° C., trifluoroacetic acid (1.5 mL,1.34 mmol) was added and stirred at 25° C. for 16 h. The solvent wasremoved under reduced pressure and the mixture made basic with theresidue with aqueous ammonia. Filtration and washing with diethyl etherprovided (6-[(E)-2-cyclopropylvinyl]pyrimidin-4-amine (4) as a brownsolid. Yield: 170 mg, 79%; MS (ESI) m/z 162.10 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 8.19 (s, 1H), 6.70 (brs, 2H), 6.32-6.27 (m, 2H), 6.17 (s,1H), 1.60 (m, 1H), 0.84 (m, 2H), 0.55 (m, 2H).

Synthesis of6-[[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 31)

The synthesis of compound 31 was carried out as described above usingthe general protocol of Procedure B. Light brown solid; Yield: 70 mg,19%; MS (ESI) m/z 392.26 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (brs,1H), 9.42 (s, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.63 (s, 1H), 7.19 (s, 1H),7.00 (d, J=8.0 Hz, 1H), 6.46 (m, 2H), 2.13 (s, 3H), 1.69 (m, 1H), 0.90(m, 2H), 0.62 (m, 2H).

Example 32 Synthesis of3,3-dimethyl-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 32)

Synthesis of3,3-dimethyl-6-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 32)

The synthesis of compound 32 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.13 g, 42%;MS (ESI) m/z 296[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.1 (s, 1H), 9.15(s, 1H), 8.83 (s, 1H), 8.18-8.27 (m, 1H), 7.98-7.87 (m, 1H), 6.99 (d,J=5.9 Hz, 1H), 6.87 (d, J=7.7 Hz, 1H), 1.88 (s, 6H).

Example 33 Synthesis of3-(3,5-dichlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 33)

Synthesis of6-chloro-3-(3,5-dichlorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.21 g, 21%.

Synthesis of3-(3,5-dichlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 33)

The synthesis of compound 33 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.042 g, 17%;MS (ESI) m/z 402[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 9.38(s, 1H), 8.85-8.74 (m, 2H), 8.36 (d, J=5.9 Hz, 1H), 7.66 (t, J=1.9 Hz,1H), 7.44 (d, J=1.9 Hz, 2H), 7.29 (d, J=6.0 Hz, 1H), 7.02 (d, J=7.7 Hz,1H), 2.23 (s, 3H).

Example 34 Synthesis of3-methyl-3-(pyridin-2-yl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 34)

Synthesis of6-chloro-3-methyl-3-(pyridin-2-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.26 g, 33%; MS (ESI) m/z276[M+1]⁺.

Synthesis of3-methyl-3-(pyridin-2-yl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 34)

The synthesis of compound 34 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 0.012 g,5%; MS (ESI) m/z 335.10[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.96 (s, 1H),9.28 (s, 1H), 8.83-8.73 (m, 2H), 8.55-8.48 (m, 1H), 8.34 (d, J=5.9 Hz,1H), 7.88-7.84 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.37 (dd, J=7.6, 4.7 Hz,1H), 7.25 (d, J=5.9 Hz, 1H), 6.97 (d, J=7.6 Hz, 1H), 2.29 (s, 3H).

Example 35 Synthesis of8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 35)

Synthesis of6-bromo-8-chloro-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 1.8 g, 66%;MS (ESI) m/z 346.6 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H),8.36 (s, 1H), 2.06 (s, 3H).

Synthesis of8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-(trifluoromethyl)-2H-imidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 35)

The synthesis of compound 35 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 0.52 g,35%; MS (ESI) m/z 360.22 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.60 (s,1H), 9.82 (s, 1H), 8.87 (s, 1H), 8.81 (m, 1H), 8.47 (d, J=6.0 Hz, 1H),7.46 (d, J=6.0 Hz, 1H), 2.12 (s, 3H).

Example 36 Synthesis of2′,2′-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(Cpd. No. 36)

Synthesis of6-chloro-2′,2′-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Cream colored solid; Yield: 0.12 g,16%; MS (ESI) m/z 267.15 [M+1]⁺.

Synthesis of2′,2′-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(Cpd. No. 36)

The synthesis of compound 36 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 17 mg, 9%;MS (ESI) m/z 326.30[M+1]⁺; 1H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H),9.48 (s, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J=6.0 Hz,1H), 7.40 (d, J=6.06 Hz, 1H), 6.87 (d, J=7.6 Hz, 1H), 2.94 (m, 1H),2.50-1.66 (m, 6H), 1.03 (s, 3H), 0.72 (s, 3H).

Example 37 Synthesis of6-[(8-cyclopropyl-9H-purin-6-yl)amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 37)

Synthesis of 6-chloro-8-cyclopropyl-9H-purine (3)

To a solution of 6-chloropyrimidine-4,5-diamine (1, 2.0 g, 13.84 mmol)and cyclopropanecarbaldehyde (2, 1.16 g, 16.6 mmol) in methanol (100mL), acetic acid (1.0 mL) was added and stirred at room temperature for2 h. To this mixture was added iron(III) chloride (11.22 g, 69.18 mmol)and stirring was continued for 24 h. The solvents were removed underreduced pressure and the crude residue was purified via columnchromatography (silica, ethyl acetate/hexanes=70%) to afford6-chloro-8-cyclopropyl-9H-purine (3) as a white solid. Yield: 1.2 g,45%; MS (ESI) m/z 195.14 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.65 (s,1H), 8.60 (s, 1H), 2.19 (m, 1H), 1.18 (m, 4H).

Synthesis of2-[(6-chloro-8-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane (5)

To a stirred suspension of sodium hydride (0.18 g, 7.71 mmol) indimethylformamide (10 mL) at 0° C., 6-chloro-8-cyclopropyl-9H-purine (3,1.0 g, 5.14 mmol) was added and stirred for 30 m. To this mixture,2-(chloromethoxy)ethyl-trimethyl-silane (4, 2.0 mL, 6.17 mmol) was addeddropwise and allowed to stir at room temperature for 16 h. The reactionmixture was quenched with ice cold water (20 mL) and extracted withethyl acetate (3×50 mL). The combined organic layers were separated anddried with magnesium sulfate before concentration to dryness. The cruderesidue was purified via column chromatography ethylacetate/hexanes=70%) to afford2-[(6-chloro-8-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane (5)as an off-white solid. Yield: 0.84 g, 50%; MS (ESI) m/z 325.30 [M+1]⁺;¹H NMR (400 MHz, CDCl₃) δ 8.65 (s, 1H), 5.73 (s, 2H), 3.61 (m, 2H), 2.44(m, 1H), 1.43 (m, 2H), 1.26 (m, 2H), 0.88 (m, 2H), 0.05 (s, 9H).

Synthesis of 8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-amine(6)

In a sealed tube a stirred suspension of2-[(6-chloro-8-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane (5,0.8 g, 2.46 mmol) and 30% aqueous ammonia (10 mL) in ethanol (10 mL) washeated at 120° C. for 14 h. After TLC showed consumption of 5, ethanolwas removed under reduced pressure and the residue was washed with water(10 mL) and diethyl ether (10 mL) to obtain8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-amine (6) as awhite solid. Yield: 703 mg, 93%; MS (ESI) m/z 306.30 [M+1]⁺; ¹H NMR (400MHz, CDCl₃) δ 8.00 (s, 1H), 7.10 (s, 2H), 5.64 (s, 2H), 3.57 (m, 2H),2.24 (m, 1H), 1.08 (m, 4H), 0.83 (m, 2H), 0.09 (s, 9H).

Synthesis of6-[[8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-yl]amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(8)

The synthesis of intermediate 8 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 300 mg, 50%;MS (ESI) m/z 536.26 [M+1]⁺.

Synthesis of6-[(8-cyclopropyl-9H-purin-6-yl)amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 37)

To a solution of6-[[8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-yl]amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(8, 0.25 g, 0.47 mmol) in tetrahydrofuran (50 mL) was addedtetrabutylammonium fluoride hydrate (0.61 g, 2.33 mmol). The mixture washeated at 70° C. for 4 h. After TLC showed consumption of 8, thereaction mixture was diluted with water (50 mL) and extracted with ethylacetate (2×50 mL). The combined organic layers were dried over sodiumsulfate and concentrated under reduced pressure. The crude mixture waspurified via column chromatography (silica, methanol/dichloromethane=2%)to afford6-[(8-cyclopropyl-9H-purin-6-yl)amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 37) as yellow solid. Yield: 135 mg, 71%; MS (ESI) m/z 406.29[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 13.24 (s, 1H), 10.55 (s, 1H), 8.80(d, J=7.6 Hz, 1H), 8.64 (s, 1H), 8.49 (s, 1H), 7.10 (d, J=7.6 Hz, 1H),2.16 (m, 1H), 2.15 (s, 3H), 1.12 (m, 4H).

Example 38 Synthesis ofN-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 38)

Synthesis of ethyl 5-bromo-3-chloro-pyridine-2-carboxylate (2)

To a stirred solution of 5-bromo-3-chloro-pyridine-2-carboxylic acid (1,150.0 g, 634.38 mmol) in ethanol (1.5 L) was added sulfuric acid (93.26g, 951.58 mmol) at room temperature. The reaction mass was stirred at80° C. overnight. After consumption of starting material as indicated byTLC, the reaction mixture was cooled to room temperature and solvent wasremoved under reduced pressure. The resulting residue was neutralizedwith saturated aqueous sodium bicarbonate solution and extracted withethyl acetate (2×1 L). The organic layers were then separated, combined,dried with magnesium sulfate and concentrated to dryness in vacuum toafford ethyl 5-bromo-3-chloro-pyridine-2-carboxylate (2) as an off whitesolid. Yield: 163 g, 97%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (m, 1H), 8.08(m, 1H), 7.81 (m, 1H), 4.47 (m, 2H), 1.43 (t, J=7.2 Hz, 3H).

Synthesis of ethyl 5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate(3)

To a stirred solution of ethyl 5-bromo-3-chloro-pyridine-2-carboxylate(2, 151.0 g, 570.89 mmol) in dichloromethane (1.73 L) was addedtrifluoroacetic anhydride (30.0 mL, 1.14 mol) and urea hydrogen peroxide(112.69 g, 1.20 mol) at 0° C. The reaction was stirred overnight at roomtemperature. After completion of the reaction, the reaction mixture wasneutralized with a potassium phosphate dibasic solution. A sodiumbisulfite solution was added followed by extraction with dichloromethane(2×100 mL). The organic layers were separated, combined, dried withmagnesium sulfate, filtered and concentrated to dryness under vacuum toafford ethyl 5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate 3 asan off white solid. Yield: 150.5 g, 94%; MS (ESI) m/z 281.8 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.26 (d, J=1.2 Hz, 1H), 7.48 (d, J=1.2 Hz, 1H),4.50 (q, J=7.12 Hz, 2H), 1.42 (t, J=12.12 Hz, 3H).

Synthesis of ethyl 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4)

To a stirred solution of ethyl5-bromo-3-chloro-1-oxido-pyridin-1-ium-2-carboxylate (3, 150 g, 534.8mmol) in dimethylformamide (900 mL) at 0° C. was added trifluoroaceticanhydride (224.63 g, 1.07 mmol). The temperature of the reaction mixturewas raised to 50° C. and stirring was continued for 1 h. After theoxidation was complete, the reaction mass was quenched with a saturatedaqueous sodium bicarbonate solution and product was extracted withdichloromethane (2×100 mL). The organic layers were separated, combined,dried with magnesium sulfate and concentrated to dryness under vacuum toafford ethyl 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4) as ayellow solid. Yield: 75 g, 50%; MS (ESI) m/z 281.8 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 10.44-10.02 (m, 1H), 7.86 (s, 1H), 4.47 (q, J=7.2 Hz,2H), 1.43 (t, J=5.6 Hz, 3H).

Synthesis of 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (5)

In a round bottom flask containing ethyl5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxylate (4, 75.0 g, 267.38mmol) was added liquid ammonia (150.0 mL, 267.38 mmol) in ethanol (100mL) at 0° C. The reaction mixture was stirred at 45° C. for 2 h. At thistime the mixture was concentrated to remove the ethanolic ammonia. Thecrude solids were washed with diethyl ether (500 mL) and dissolved inrefluxing methanol (1 L) and filtered hot. The filtrate was concentratedunder reduced pressure until 1/3 of solvent volume remained. Diethylether was added until all solids precipitated. The solid was filteredand dried under vacuum to afford5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (5) as a light brownsolid. Yield: 45 g, 69%; MS (ESI) m/z 248.9 [M−1]⁻; ¹H NMR (400 MHz,DMSO-d₆) δ 7.92-7.82 (m, 1H), 7.61-7.59 (m, 1H), 7.36 (s, 1H).

Synthesis6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(7)

The synthesis of intermediate 7 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 450 mg,87%; MS (ESI) m/z 317.03 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s,1H), 8.25 (s, 1H), 2.73 (m, 4H), 2.21 (m, 2H), 1.93 (m, 2H).

Synthesis ofN-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 38)

The synthesis of compound 38 was carried out as described above usingthe general protocol of Procedure B. White solid; Yield: 50 mg, 17%; MS(ESI) m/z 415.32 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H),10.08 (s, 1H), 9.52 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 7.98 (s, 1H),2.78 (m, 2H), 2.02 (m, 3H), 1.83 (m, 2H), 1.72 (m, 2H), 0.84 (d, J=6.0Hz, 4H).

Example 39 Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 39)

Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 39)

The synthesis of compound 39 was carried out as described above usingthe general protocol of Procedure B. Off white solid; Yield: 0.07 g,30%; MS (ESI) m/z 332.28 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s,1H), 9.67 (s, 1H), 8.84 (s, 1H), 8.79 (s, 1H), 8.43 (d, J=5.6 Hz, 1H),7.43 (d, J=5.6, 1H), 2.77 (m, 2H), 1.98 (m, 2H), 1.82 (m, 2H), 1.74 (m,2H).

Example 40 Synthesis of3,3-dimethyl-6-(5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 40)

Synthesis of3,3-dimethyl-6-(5H-pyrrolo[2,3-d]pyrimidin-7(6H)-yl)-2,3-dihydroimidazo-[1,5-a]pyridine-1,5-dione(Cpd. No. 40)

To a stirred solution of 3, 3-dimethyl-6-(7H-pyrrolo [2, 3-d]pyrimidin-7-yl)-2, 3-dihydroimidazo[1,5-a]pyridine-1,5-dione (1, 0.095g, 0.32 mmol) in methanol (25 ml), 10% palladium on carbon (25 mg) wasadded. The reaction mixture was hydrogenated under balloon pressurehydrogen gas for 24 h. The progress of the reaction was monitored byTLC. After complete consumption of starting material, reaction mixturewas filtered through a pad of celite and the filtrate was concentratedunder reduced pressure to obtain a crude residue. The residue waspurified by prep HPLC to afford the product as a light yellow solid.Yield: 8.0 mg, 8%; MS (ESI) m/z 298.20 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆)δ 8.35 (s, 1H), 8.15 (s, 1H), 7.96 (d, J=7.4 Hz, 1H), 6.81 (d, J=7.5 Hz,1H), 4.17 (t, J=8.6 Hz, 2H), 3.13 (t, J=8.6 Hz, 2H), 2.59 (s, 2H), 1.79(s, 6H).

Example 41 Synthesis of3-(2-aminoethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 41)

Synthesis of6-chloro-3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 3.01 g, 59%; MS(ESI) m/z 372.0 [M+1]⁺.

Synthesis of3-[2-(1,3-dioxoisoindolin-2-yl)ethyl]-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 1.03 g, 36%;MS (ESI) m/z 431.31 [M+1]⁺.

Synthesis of3-(2-aminoethyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 41)

The synthesis of compound 41 was carried out as described above usingthe general protocol of Procedure C. Cream-colored solid; Yield: 300 mg,54%; MS (ESI) m/z 301.32 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (brs,1H), 8.77 (d, J=7.6 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J=6.0 Hz, 1H), 7.37(d, J=5.6 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 4.39 (brs, 2H), 2.59 (m, 1H),2.41 (m, 1H), 2.22 (m, 1H), 2.15 (m, 1H), 1.80 (s, 3H).

Example 42 Synthesis ofN-[6-[(8-chloro-3-cyclopentyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 42)

Synthesis of6-bromo-8-chloro-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Light brown solid; Yield: 605 mg,54%; MS (ESI) m/z 346.98 [M+1]⁺.

Synthesis ofN-[6[(8-chloro-3-cyclopentyl-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 42)

The synthesis of compound 42 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 16 mg, 5%;MS (ESI) m/z 443.35 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H),9.78 (s, 1H), 9.46 (s, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 7.97 (s, 1H),3.39 (m, 1H), 2.01 (m, 1H), 1.82 (s, 3H), 1.77 (m, 1H), 1.57-1.37 (m,5H), 1.14 (m, 1H), 0.83 (m, 5H).

Example 43 Synthesis ofN-[6-[(8-chloro-3,3-dimethyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 43)

Synthesis of6-bromo-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 390 mg, 48%; MS(ESI) m/z 288.93 [M−1]⁻; ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.24(s, 1H), 1.75 (s, 6H).

Synthesis ofN-[6[(8-chloro-3,3-dimethyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)-amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 43)

The synthesis of compound 43 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 42 mg,17%; MS (ESI) m/z 389.28 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s,1H), 9.74 (s, 1H), 9.49 (s, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 7.98 (s,1H), 2.02 (m, 1H), 1.79 (s, 6H), 0.84 (d, J=6.0 Hz, 4H).

Example 44 Synthesis ofN-(6-((8′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclobutane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 44)

Synthesis of6′-bromo-8′-chloro-2′H-spiro[cyclobutane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 0.260 g, 72%;MS (ESI) m/z 300.94 [M−1]⁻; ¹H NMR (400 MHz, DMSO-d₆) δ 10.5 (s, 1H),8.24 (s, 1H), 3.45 (m, 2H), 2.28 (m, 2H), 2.10 (m, 1H), 1.89 (m, 1H).

Synthesis ofN-(6-((8′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclobutane-1,3′-imidazo-[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No, 44)

The synthesis of compound 44 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.110 g,33%; MS (ESI) m/z 401.27 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s,1H), 10.24 (s, 1H), 9.59 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 8.00 (s,1H), 3.26 (m, 2H), 2.34 (m, 2H), 2.15 (m, 1H), 2.04 (m, 1H), 1.89 (m,1H), 0.82 (m, 4H).

Example 45 Synthesis ofN-(6-((8′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 45)

Synthesis of6′-bromo-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 1.93 g,64%; MS (ESI) m/z 330.99 [M+1]; ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s,1H), 8.24 (s, 1H), 2.84 (t, J=10.74, 2H), 1.74 (m, 2H), 1.63 (m, 3H),1.53 (m, 2H), 1.20 (m, 1H).

Synthesis ofN-(6-((8′-chloro-1,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 45)

The synthesis of compound 45 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.051 g,2.07%; MS (ESI) m/z 429.34 [M+1]+; ¹H NMR (400 MHz, DMSO-d6) δ 10.93 (s,1H), 10.29 (s, 1H), 9.43 (s, 1H), 8.70 (s, 1H), 8.58 (s, 1H), 7.97 (s,1H), 2.93 (t, J=11.16 Hz, 2H), 2.02 (m, 1H), 1.75 (m, 2H), 1.64 (m, 3H),1.54 (m, 2H), 1.21 (m, 1H), 0.84 (m, 4H).

Example 46 Synthesis ofN-[6-[[8-chloro-3-methyl-1,5-dioxo-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 46)

Synthesis of6-bromo-8-chloro-3-methyl-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]-pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 325 mg, 57%; MS(ESI) m/z 358.95 [M+1]⁺.

Synthesis ofN-[6-[[8-chloro-3-methyl-1,5-dioxo-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 46)

The synthesis of compound 46 was carried out as described above usingthe general protocol of Procedure B. Light brown solid; Yield: 120 mg,32%; MS (ESI) m/z 457.31 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,1H), 9.92 (s, 1H), 9.59 (s, 1H), 8.75 (s, 1H), 8.60 (s, 1H), 8.01 (s,1H), 3.69 (m, 1H), 3.12 (m, 1H), 2.02 (m, 1H), 1.87 (s, 3H), 0.84 (d,J=6.0 Hz, 4H).

Example 47 Synthesis of8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 47)

Synthesis of8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 47)

The synthesis of compound 47 was carried out as described above usingthe general protocol of Procedure B. Off white solid; Yield: 0.020 g,10%; MS (ESI) m/z 306.25 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s,1H), 9.64 (s, 1H), 8.84 (s, 1H), 8.79 (s, 1H), 8.43 (d, J=5.6 Hz, 1H),7.44 (d, J=5.2 Hz, 1H), 1.81 (s, 6H).

Example 48 Synthesis of8-chloro-3-cyclopentyl-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 48)

Synthesis of8-chloro-3-cyclopentyl-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 48)

The synthesis of compound 48 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.019 g,6%; MS (ESI) m/z 360.23 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s,1H), 9.63 (s, 1H), 8.84 (s, 1H), 8.79 (s, 1H), 8.44 (d, J=5.7 Hz, 1H),7.43 (d, J=5.6 Hz, 1H), 3.38 (m, 1H), 1.84 (s, 3H), 1.79 (m, 1H), 1.51(m, 5H), 1.13 (m, 1H), 0.83 (m, 1H).

Example 49 Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(trifluoromethyl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 49)

Synthesis of6-bromo-8-chloro-3-methyl-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Light brown solid; Yield: 0.7 g,crude; MS (ESI) m/z 342.97 [M−1]⁻

Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(trifluoromethyl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 49)

The synthesis of compound 49 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid. Yield: 0.16 g,42%; MS (ESI) m/z 443.27 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,1H), 10.55 (bs, 1H), 9.72 (s, 1H), 8.74 (s, 1H), 8.61 (s, 1H), 8.04 (s,1H), 2.11 (s, 3H), 2.03 (m, 1H), 0.84 (d, J=6.0 Hz, 4H).

Example 50 Synthesis ofN-[6-[(8-chloro-4′,4′-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 50)

Synthesis of6-bromo-8-chloro-4′,4′-difluoro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 0.41 g,93%; MS (ESI) m/z 366.94 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s,1H), 7.89 (s, 1H), 2.12 (m, 6H), 1.66 (m, 2H).

Synthesis ofN-[6[(8-chloro-4′,4′-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 50)

The synthesis of compound 50 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.098 g,39%; MS (ESI) m/z 465.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s,1H), 10.47 (s, 1H), 9.52 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 7.98 (s,1H), 3.30-3.20 (m, 2H), 2.35-2.15 (m, 4H), 2.05-1.98 (m, 1H), 1.75-1.67(m, 2H), 0.97-0.80 (m, 4H).

Example 51 Synthesis ofN-[6-[[8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 51)

Synthesis of6-bromo-8-chloro-3-(3-chlorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 0.13 g, 17%; MS(ESI) m/z 386.83 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 8.32(s, 1H), 7.52 (s, 1H), 7.43 (m, 2H), 7.34 (d, J=7.6 Hz, 1H), 2.18 (s,3H).

Synthesis ofN-[6-[[8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 51)

The synthesis of compound 51 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.04 g,25%; MS (ESI) m/z 485.30 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s,1H), 10.09 (s, 1H), 9.44 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 7.90 (s,1H), 7.52 (s, 1H), 7.43 (m, 2H), 7.34 (d, J=7.2 Hz, 1H), 2.23 (s, 3H),2.00 (m, 1H), 0.82 (m, 4H).

Example 52 Synthesis ofN-[6-[[8-chloro-3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 52)

Synthesis of6-bromo-8-chloro-3-(3-fluorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 0.18 g, 20%; MS(ESI) m/z 373.01 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 8.31(s, 1H), 7.43 (m, 1H), 7.31 (d, J=10.3 Hz, 1H), 7.22 (m, 2H), 2.19 (s,3H).

Synthesis ofN-[6-[[8-chloro-3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 52)

The synthesis of compound 52 was carried out as described above usingthe general protocol of Procedure B. White solid; Yield: 0.035 g, 15%;MS (ESI) m/z 469.34 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H),10.10 (s, 1H), 9.44 (s, 1H), 8.75 (s, 1H), 8.59 (s, 1H), 7.90 (s, 1H),7.42 (m, 1H), 7.32 (m, 1H), 7.23 (m, 2H), 2.23 (s, 3H), 2.00 (m, 1H),0.823 (m, 4H).

Example 53 Synthesis of(3'S)-3′-amino-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 53)

Synthesis of 2-[(1S,3R)-3-hydroxycyclohexyl]isoindoline-1,3-dione (3)

To a solution of (1R,3S)-3-aminocyclohexanol hydrochloride (2, 1.0 g,6.57 mmol) in water (50 mL) at 0° C., ethyl1,3-dioxoisoindoline-2-carboxylate (1, 1.6 g, 7.3 mmol) was added. Themixture was allowed to stir at 25° C. for 3 hours while monitoring byTLC. After completion, the suspension was filtered and the residue waswashed with water (50 mL) and dried to obtain2-[(3R)-3-hydroxycyclohexyl]isoindoline-1,3-dione (3) as a white solid.Yield: 1.45 g, 81%; ¹H NMR (400 MHz, DMSO-d₆) δ 7.83 (m, 4H), 4.77 (m,1H), 3.99 (m, 1H), 2.04-1.29 (m, 9H).

Synthesis of (S)-2-(3-oxocyclohexyl)isoindoline-1,3-dione (4)

To a stirred solution of2-[(3R)-3-hydroxycyclohexyl]isoindoline-1,3-dione (3, 1.4 g, 5.71 mmol)in dichloromethane (50 mL) at 0° C., was added pyridinium chlorochromate(3.69 g, 17.12 mmol). The mixture was allowed to stir at 25° C. for 5hours while monitoring by TLC. The reaction mixture was made basic (pH8) with saturated aqueous sodium bicarbonate solution and extracted withdichloromethane (2×150 mL). The combined organic layers were dried oversodium sulfate and concentrated under reduced pressure to obtain2-(3-oxocyclohexyl)isoindoline-1,3-dione (4) as a brown solid. Yield:1.31 g, 94%; MS (ESI) m/z 244.15 [M+1]⁺.

Synthesis of(3'S)-6-chloro-3′-(1,3-dioxoisoindolin-2-yl)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure A. Cream colored solid; Yield: 1.51 g,71%; MS (ESI) m/z 398.19 [M+1]⁺.

Synthesis of(3'S)-3′-(1,3-dioxoisoindolin-2-yl)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(8)

The synthesis of intermediate 8 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 104 mg, 45%;MS (ESI) m/z 457.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.54 (s, 1H),9.47 (s, 1H), 8.76 (s, 2H), 8.37 (s, 1H), 7.84 (m, 4H), 7.38 (s, 1H),6.91 (m, 1H), 4.60 (m, 1H), 3.96 (m, 1H), 3.32 (m, 1H), 3.06 (m, 1H),2.32 (m, 1H), 1.99-1.56 (m, 5H).

Synthesis of(3'S)-3′-amino-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 53)

The synthesis of compound 53 was carried out as described above usingthe general protocol of Procedure C. Pale greenish solid; Yield: 60.0mg, 21%; MS (ESI) m/z 327.35 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 9.37(s, 1H), 8.78 (d, J=7.6 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J=6.0 Hz, 1H),7.37 (d, J=5.6 Hz, 1H), 6.89 (d, J=7.6 Hz, 1H), 2.89 (m, 2H), 2.72 (m,1H), 1.82 (m, 2H), 1.65 (m, 2H), 1.46 (m, 1H), 1.05 (m, 1H).

Example 54 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dionehydrochloride (Cpd. No. 54)

Synthesis of tert-butyl8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.08 g,50%; MS (ESI) m/z 447.17 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s,1H), 9.63 (s, 1H), 8.85 (s, 1H), 8.79 (s, 1H), 8.44 (d, J=5.8 Hz, 1H),7.45 (d, J=5.6 Hz, 1H), 4.14 (m, 2H), 3.89 (m, 1H), 3.05 (m, 1H), 2.90(m, 1H), 1.93 (m, 3H), 1.41 (s, 9H).

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dionehydrochloride (Cpd. No. 54)

The synthesis of compound 54 was carried out as described above usingthe general protocol of Procedure D. Light brown solid; Yield: 0.024 g,35%; MS (ESI) m/z 347.31 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (s,1H), 9.99 (s, 1H), 9.72 (bs, 1H), 9.48 (bs, 1H), 8.99 (bs, 1H), 8.78 (s,1H), 8.53 (bs, 1H), 7.54 (bs, 1H), 4.15 (m, 1H), 3.52 (m, 1H), 3.38 (m,1H), 3.03 (m, 1H), 2.92 (m, 1H), 2.17 (m, 1H), 2.04 (m, 1H), 1.84 (m,1H).

Example 55 Synthesis of8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 55)

Synthesis of8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-(2,2,2-trifluoroethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 55)

The synthesis of compound 55 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.1 g,30%; MS (ESI) m/z 374.25 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.95 (s,1H), 9.70 (s, 1H), 8.86 (s, 1H), 8.83 (s, 1H), 8.45 (d, J=5.6 Hz, 1H),7.45 (d, J=5.6 Hz, 1H), 3.73 (m, 1H), 3.14 (m, 1H), 1.89 (s, 3H).

Example 56 Synthesis ofN-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamidehydrochloride (Cpd. No. 56)

Synthesis of tert-butyl6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(3)

Procedure E: To a stirred solution of5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.4 g, 1.59 mmol)in 1,4-dioxane (12 mL) was added tert-butyl4-oxopiperidine-1-carboxylate (2, 1.58 g, 7.95 mmol) in a vial at roomtemperature. Concentrated sulfuric acid (0.16 g, 1.59 mmol) was thenadded dropwise. The vial was sealed and heated to 120° C. for 3 h. Thereaction mixture was quenched with water (20 mL) and extracted withethyl acetate (2×15 mL). The organic layers were separated and theaqueous layer was diluted with 1,4-dioxane (30 mL), water (25 mL) andtreated with di-tert-butyl dicarbonate (0.44 g, 2.03 mmol) dropwise at0° C. The reaction mixture was stirred at room temperature overnight.After consumption of starting material the reaction was extracted with10% methanol in dichloromethane (2×25 mL). The organic layers were driedwith magnesium sulfate, filtered and concentrated to dryness. The cruderesidue was then purified by flash column chromatography using neutralalumina eluting with 2% methanol in dichloromethane. The desiredfractions were concentrated to dryness in vacuo to afford tert-butyl6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(3) as a yellow solid. Yield: 0.26 g, 44%; MS (ESI) m/z 430.11 [M−1]⁻;¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 8.27 (m, 1H), 4.04 (s, 2H),2.92 (m, 4H), 1.57 (m, 2H), 1.42 (s, 9H).

Synthesis of tert-butyl8-chloro-6-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate (5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.14 g, 44%;MS (ESI) m/z 530.36 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H),10.49 (s, 1H), 9.51 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.00 (s, 1H),4.05 (m, 2H), 3.20 (m, 1H), 3.09 (m, 3H), 2.02 (m, 1H), 1.58 (m, 2H),1.43 (s, 9H), 0.84 (m, 4H).

Synthesis ofN-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamidehydrochloride (Cpd. No. 56)

The synthesis of compound 56 was carried out as described above usingthe general protocol of Procedure D. Yellow solid; Yield: 0.10 g, 87%;MS (ESI) m/z 430.38 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.98 (s, 1H),10.54 (s, 1H), 9.43 (s, 1H), 9.33 (d, J=9.6 Hz, 1H), 8.77 (d, J=11.6 Hz,1H), 8.73 (s, 1H), 8.60 (s, 1H), 8.00 (s, 1H), 3.48 (s, 2H), 3.32 (m,2H), 3.18 (m, 2H), 2.02 (m, 1H), 1.86 (d, J=12.4 Hz, 2H), 0.84 (m, 4H).

Example 57 Synthesis of8-chloro-3-(3-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 57)

Synthesis of8-chloro-3-(3-fluorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 57)

The synthesis of compound 57 was carried out as described above usingthe general protocol of Procedure B. White solid; Yield: 0.025 g, 10%;MS (ESI) m/z 386.31 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1H),9.56 (s, 1H), 8.84 (s, 1H), 8.82 (s, 1H), 8.41 (d, J=5.9 Hz, 1H), 7.42(m, 1H), 7.33 (m, 2H), 7.22 (m, 2H), 2.24 (s, 3H).

Example 58 Synthesis of8-chloro-3-(3-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 58)

Synthesis of8-chloro-3-(3-chlorophenyl)-3-methyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 58)

The synthesis of compound 58 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.07 g,32%; MS (ESI) m/z 402.25 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.14 (s,1H), 9.57 (s, 1H), 8.84 (s, 1H), 8.82 (s, 1H), 8.41 (d, J=5.9 Hz, 1H),7.54 (s, 1H), 7.43 (m, 2H), 7.35 (m, 2H), 2.24 (s, 3H).

Example 59 Synthesis of6-((6-((1-cyclopropyl-2,2,2-trifluoroethyl)amino)pyrimidin-4-yl)amino)-3-methyl-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 59)

Synthesis of tert-butylN-tert-butoxycarbonyl-N-[6[(1-cyclopropyl-2,2,2-trifluoroethyl)amino]pyrimidin-4-yl]carbamate(3)

To a solution of tert-butylN-tert-butoxycarbonyl-N-(6-chloropyrimidin-4-yl)carbamate (1, 0.50 g,1.52 mmol) and 1-cyclopropyl-2,2,2-trifluoro-ethanamine hydrochloride(2, 0.40 g, 2.27 mmol) in monoglyme (15 mL) in a vial, sodiumtert-butoxide (0.729 g, 7.58 mmol) was added. After purging with argongas for 30 minutes, BINAP (0.14 g, 0.23 mmol) andtris(dibenzylideneacetone)dipalladium(0) (69 mg, 0.080 mmol) were added.The vial was sealed and the contents heated at 90° C. for 24 h. Solventwas removed and the crude mixture was by flash chromatography elutingwith a 10-12% gradient of Ethyl acetate in hexane. The desired fractionswere concentrated under pressure to obtain tert-butylN-tert-butoxycarbonyl-N-[6-[(1-cyclopropyl-2,2,2-trifluoro-ethyl)amino]pyrimidin-4-yl]-carbamate(3) as an off-white solid. Yield: 110 mg, 17%; ¹H NMR (400 MHz, DMSO-d₆)δ 9.78 (s, 1H), 8.15 (s, 1H), 7.79 (d, J=9.2 Hz, 1H), 7.10 (s, 1H), 4.47(m, 1H), 1.46 (s, 1H), 0.61 (m, 1H), 0.49 (m, 2H), 0.39 (m, 1H).

Synthesis ofN⁴-(1-cyclopropyl-2,2,2-trifluoro-ethyl)pyrimidine-4,6-diaminehydrochloride (4)

Procedure F: To a solution of tert-butylN-tert-butoxycarbonyl-N-[6-[(1-cyclopropyl-2,2,2-trifluoro-ethyl)amino]pyrimidin-4-yl]-carbamate(3, 250 mg, 0.58 mmol) in dichloromethane (2 mL) and methanol (2 mL) wasadded 4 M hydrogenchloride in 1,4-dioxane (5 mL). The reaction wasstirred at room temperature overnight. The solvents were evaporatedunder reduced pressure, the resultant residue was triturated withdichloromethane. The solids were placed in a round bottom flask andaqueous ammonia was added adjusting the pH to 8-9. The solvent contentwas reduced added and water was added. The solids were filtered anddried to affordN⁴-(1-cyclopropyl-2,2,2-trifluoro-ethyl)pyrimidine-4,6-diaminehydrochloride (4) as a light brown solid. Yield: 130 mg, crude; MS (ESI)m/z 233 [M+1-HCl]⁺.

Synthesis of6-[[6-[(1-cyclopropyl-2,2,2-trifluoro-ethyl)amino]pyrimidin-4-yl]amino]-3-methyl-3-(trifluoromethyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 59)

The synthesis of compound 59 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 33 mg, 19%;MS (ESI) m/z 463.36 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (brs, 1H),9.05 (s, 1H), 8.62 (d, J=7.6 Hz, 1H), 8.26 (s, 1H), 7.80 (d, J=8.8 Hz,1H), 6.96 (d, J=8.0 Hz, 1H), 6.43 (s, 1H), 4.36 (brs, 1H), 2.12 (s, 3H),1.12 (m, 1H), 0.67 (m, 1H), 0.51 (m, 2H), 0.35 (m, 1H).

Example 60 Synthesis ofN-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamidehydrochloride (Cpd. No. 60)

Synthesis of tert-butyl6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate(3)

To a stirred solution of5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.7 g, 2.78 mmol)in 1,4-dioxane (10 mL) in a vial, piperidin-3-one hydrochloride (2, 1.13g, 8.35 mmol) was added at room temperature. To this solutionconcentrated sulfuric acid (0.27 g, 2.78 mmol) was added dropwise. Thereaction vial was sealed and heated to 100° C. for 48 h. Aftercompletion the solvent was removed under reduced pressure and theresultant reaction mass was diluted with water (20 mL) and the aqueouslayer was washed with ethyl acetate (3×20 mL). The aqueous solution(20.0 mL) of6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(˜0.5 g) was treated with sodium hydroxide (90 mg, 2.26 mmol).di-tert-butyl dicarbonate (0.39 g, 1.80 mmol) in 1,4-dioxane (20 mL) wasadded and the reaction mixture was stirred at 25° C. for 6 h. Oncecompleted the solvent was removed under reduced pressure. The aqueouslayer was extracted with ethyl acetate (2×25 mL) and the organic layerswere washed with water (2×10 mL). The organic layers were separated anddried with sodium sulfate, filtered and concentrated to dryness. Thecrude residue was purified by flash column chromatography eluting with2% methanol in dichloromethane. The desired fractions were concentratedto dryness to afford tert-butyl6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate(3) as white solid. Yield: 0.4 g; MS (ESI) m/z 432 [M+1]⁺.

Synthesis of tert-butyl8-chloro-6-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate (5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.07 g,19%; MS (ESI) m/z 530.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s,1H), 9.48 (s, 1H), 8.72 (s, 1H), 8.60 (s, 1H), 7.99 (s, 1H), 4.05 (m,2H), 3.9 (m, 1H), 3.32 (m, 2H), 2.95 (m, 1H), 2.01 (m, 3H), 1.35 (s,9H), 0.84 (m, 4H).

Synthesis ofN-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamidehydrochloride (Cpd. No. 60)

The synthesis of compound 60 was carried out as described above usingthe general protocol of Procedure F. Light brown solid; Yield: 22 mg,35%; MS (ESI) m/z 430.39 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s,1H), 10.04 (s, 1H), 9.55 (s, 1H), 9.19 (bs, 1H), 8.75 (s, 1H), 8.61 (s,1H), 8.02 (s, 1H), 4.17 (m, 1H), 3.35 (m, 2H), 3.02 (m, 2H), 2.08 (m,3H), 1.81 (m, 1H), 0.84 (s, 4H).

Example 61 Synthesis ofN-(6-((8-chloro-1,5-dioxo-1,2′,3′,5,5′,6′-hexahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 61)

Synthesis of6-bromo-8-chloro-2′,3′,5′,6′-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Light brown solid; Yield: 1.0 g,crude; MS (ESI) m/z 330.8 [M−1]⁻; ¹H NMR (400 MHz, DMSO-d₆) δ 10.84 (s,1H), 8.28 (s, 1H), 3.92 (m, 2H), 3.64 (m, 2H), 3.09 (m, 2H), 1.52 (m,2H).

Synthesis ofN-(6-((8-chloro-1,5-dioxo-1,2′,3′,5,5′,6′-hexahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 61)

The synthesis of compound 61 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.11 g,21%; MS (ESI) m/z 431.36 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.94 (s,1H), 10.54 (s, 1H), 9.51 (s, 1H), 8.72 (s, 1H), 8.59 (s, 1H), 8.0 (s,1H), 3.94 (m, 2H), 3.68 (t, J=12.4 Hz, 2H), 3.19 (m, 2H), 2.05 (m, 1H),1.52 (d, J=12.4 Hz, 2H), 0.81 (d, J=6.0 Hz, 4H).

Example 62 Synthesis ofN-[6-[(8-chloro-1′,1′-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-cyclobutane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 62)

Synthesis of6-bromo-8-chloro-1′,1′-difluoro-spiro[2H-imidazo[1,5-a]pyridine-3,3′-cyclobutane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 0.4 g, 59%; MS(ESI) m/z 337 [M+1]⁺.

Synthesis ofN-[6[(8-chloro-1′,1′-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-cyclobutane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 62)

The synthesis of compound 62 was carried out as described above usingthe general protocol of Procedure B. White solid; Yield: 0.025 g, 11%;MS (ESI) m/z 437.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H),10.39 (s, 1H), 9.74 (s, 1H), 8.74 (s, 1H), 8.59 (s, 1H), 8.03 (s, 1H),4.22-4.15 (m, 1H), 3.13-2.90 (m, 1H), 2.07-1.96 (m, 1H), 0.85-0.77 (s,4H).

Example 63 Synthesis of 8-chloro-2′, 2′-dimethyl-6-(pyrimidin-4-ylamino)spiro [2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione (Cpd. No.63)

Synthesis of6-bromo-8-chloro-2′,2′-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Cream-colored solid; Yield: 0.2 g,14%; ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.29 (s, 1H), 2.96-2.91(m, 1H), 2.67 (m, 1H), 2.05-1.92 (m, 4H), 1.63-1.58 (m, 1H), 0.99 (s,3H), 0.65 (s, 3H).

Synthesis of8-chloro-2′,2′-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(Cpd. No. 63)

The synthesis of compound 63 was carried out as described above usingthe general protocol of Procedure B. Microwave reactor was used forheating in place of the conventional oil bath heating. Off white solid;Yield: 0.03 g, 29%; MS (ESI) m/z 360.29 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 9.76 (s, 1H), 9.66 (s, 1H), 8.84 (s, 1H), 8.81 (s, 1H), 8.44(d, 1H), 7.47 (d, 1H), 3.00-2.92 (m, 1H), 2.44-2.42 (m, 1H), 2.14-2.10(m, 1H), 1.99-1.90 (m, 1H), 1.65-1.62 (m, 1H), 1.02 (s, 3H), 0.67, (s,3H).

Example 64 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-2′,3′,5′,6′-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-1,5-dione(Cpd. No. 64)

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-2′,3′,5′,6′-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-1,5-dione(Cpd. No. 64)

The synthesis of compound 64 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.10 g,32%; MS (ESI) m/z 348.27 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s,1H), 9.65 (s, 1H), 8.84 (d, J=12.0 Hz, 2H), 8.44 (s, 1H), 7.47 (s, 1H),3.94 (m, 2H), 3.70 (m, 2H), 3.19 (m, 2H), 1.54 (d, J=11.4 Hz, 2H).

Example 65 Synthesis ofN-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-thietan]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 65)

Synthesis of6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-thietane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Dark brown solid; Yield: 0.25 g,20%; MS (ESI) m/z 318.96 [M−1]⁻; ¹H NMR (400 MHz, DMSO-d₆) δ 11.10 (bs,1H), 8.27 (s, 1H), 4.65 (s, 2H), 3.32 (s, 2H).

Synthesis ofN-(6-((8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-thietan]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 65)

The synthesis of compound 65 was carried out as described above usingthe general protocol of Procedure B. Off white solid; Yield: 0.05 g,30%; MS (ESI) m/z 419.26 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,1H), 10.80 (s, 1H), 9.65 (s, 1H), 8.69 (s, 1H), 8.59 (s, 1H), 8.02 (s,1H), 4.66 (s, 2H), 3.32 (s, 2H), 2.03 (m, 1H), 0.85 (s, 4H).

Example 66 Synthesis of8-chloro-2′-fluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 66)

Synthesis of6-bromo-8-chloro-2′-fluoro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Light brown solid; Yield: 0.40 g,57%; MS (ESI) m/z 349 [M−1]⁻.

Synthesis of8-chloro-2′-fluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 66)

The synthesis of compound 66 was carried out as described above usingthe general protocol of Procedure B. Off white solid; Yield: 0.1 g, 38%;MS (ESI) m/z 364.29 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.31 (s, 1H),9.65 (s, 1H), 8.85 (d, J=12 Hz, 1H) 8.45 (d, J=4 Hz, 1H) 7.46 (d, J=8Hz, 1H), 5.74-5.58 (m, 1H), 2.98-2.92 (m, 1H), 2.14-2.12 (m, 1H),1.80-1.23 (m, 1H).

Example 67 Synthesis of3,3,8-trimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 67)

Synthesis of3,3,8-trimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 67)

Procedure G: A vial was charged with8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(1, 0.20 g, 0.65 mmol), trimethylboroxine (2, 0.16 g, 1.31 mmol) andpotassium phosphate (0.28 g, 1.31 mmol) in 1,4-dioxane (10 mL) at roomtemperature under argon. Then reaction mixture was purged with argon for10 min. followed by addition of tris(dibenzylideneacetone)dipalladium(0)(60 mg, 0.07 mmol) and tricyclohexylphosphine (18 mg, 0.07 mmol). Thevial was sealed and heated at 140° C. in a microwave reactor for 1 h.The reaction mixture was concentrated to dryness and the crude residuewas subjected to flash column chromatography using silica gel 100-200mesh with a solvent gradient of 0.2-0.5% methanol in dichloromethane.The desired fractions were collected and concentrated to dryness undervacuum. The solid obtained was stirred in n-pentane and filtered. Theresulting product3,3,8-trimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 67) was obtained as an off-white solid. Yield: 0.035 g, 18%;MS (ESI) m/z 286.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s, 1H),9.39 (s, 1H), 8.77 (s, 1H), 8.60 (s, 1H), 8.37 (d, J=5.76 Hz, 1H), 7.77(d, J=5.64 Hz, 1H), 2.44 (s, 3H), 1.79 (s, 6H).

Example 68 Synthesis8-cyclopropyl-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 68)

Synthesis8-cyclopropyl-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 68)

The synthesis of compound 68 was carried out as described above usingthe general protocol of Procedure G. Off white solid; Yield: 0.032 g,16%; MS (ESI) m/z 312.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s,1H), 9.40 (s, 1H), 8.75 (s, 1H), 8.37 (d, J=5.6 Hz, 1H), 8.26 (s, 1H),7.35 (d, J=5.8 Hz, 1H), 3.17-3.15 (m, 1H), 1.80 (s, 6H), 1.10-0.98 (m,2H), 0.69-0.68 (m, 2H).

Example 69 Synthesis of8-fluoro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 69)

Synthesis of ethyl 5-bromo-3-fluoro-pyridine-2-carboxylate (2)

To a stirred solution of 5-bromo-3-fluoro-pyridine-2-carboxylic acid (1,1.0 g, 4.55 mmol) in ethanol (20 mL) was added sulfuric acid (0.67 g,6.82 mmol) at room temperature. The reaction mixture was stirred atreflux overnight. After consumption of starting materials as indicatedby TLC, the reaction mixture was cooled to room temperature, and thesolvent was removed under vacuum. The residue was neutralized with asaturated aqueous sodium bicarbonate solution and extracted with ethylacetate (2×100 mL). The organic layers were separated and dried withmagnesium sulfate, filtered and concentrated to dryness under vacuum toafford ethyl 5-bromo-3-fluoro-pyridine-2-carboxylate (2) as an off-whitesolid. Yield: 1.0 g, 89%; MS (ESI) m/z 249.9 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 8.61 (m, 1H), 7.77-7.75 (m, 1H), 4.51 (q, J=7.16 Hz, 2H),1.43 (t, J=7.12 Hz, 3H).

Synthesis of ethyl 5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate(3)

To a stirred solution of ethyl 5-bromo-3-fluoro-pyridine-2-carboxylate(2, 0.9 g, 3.63 mmol) in dichloromethane (50 mL) at 0° C. was addedtrifluoroacetic anhydride (1.52 g, 7.26 mmol), urea hydrogen peroxide(0.72 g, 7.62 mmol). The reaction mixture was stirred at roomtemperature overnight. After the oxidation was complete the reactionmixture was neutralized with a dipotassium hydrogenphosphate solutionand quenched with a sodium bisulfite solution. The product was extractedwith dichloromethane (2×100 mL). The organic layers were separated,dried with magnesium sulfate, filtered and concentrated to dryness undervacuum to afford ethyl5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate (3) as an off-whitesolid. Yield: 0.9 g, 89%; MS (ESI) m/z 265.95 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ: 8.22 (s, 1H), 7.30-7.26 (m, 1H), 4.50 (q, J=7.2 Hz, 2H),1.42 (t, J=7.2 Hz, 3H).

Synthesis of ethyl 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4)

To a stirred solution of ethyl5-bromo-3-fluoro-1-oxido-pyridin-1-ium-2-carboxylate (3, 0.85 g, 3.21mmol) in dimethylformamide (15 mL) was added trifluoroacetic anhydride(1.35 g, 6.42 mmol) at 0° C. The reaction mixture was warmed to 50° C.and stirred for 1 h, quenched with saturated aqueous sodium bicarbonatesolution and extracted with dichloromethane (2×100 mL). The organiclayers were separated, dried with magnesium sulfate, filtered andconcentrated to dryness under vacuum to afford ethyl5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4) as a yellow solid.Yield: 0.8 g, 94%; MS (ESI) m/z 264 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ7.86 (m, 1H), 4.47 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).

Synthesis of 5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxamide (5)

In a round bottom flask charged with ethyl5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxylate (4, 0.8 g, 3.03 mmol)at 0° C. was added liquid ammonia (15 mL, 3.03 mmol) in ethanol (5 mL).The stirred reaction mixture was warmed to 45° C. for 2 h. After theester was completely consumed liquid ammonia and ethanol was evaporatedunder reduced pressure. Methanol was added and the mixture was refluxedfor 2 h and filtered while hot. The volume of the filtrate was reducedby 2/3 and to the remaining methanol was added diethyl ether until solidprecipitated. The solid was filtered and dried under vacuum to afford5-bromo-3-fluoro-6-oxo-1H-pyridine-2-carboxamide (5) as a light brownsolid. Yield: 0.6 g, 85%; ¹H NMR (400 MHz, DMSO-d₆) δ 7.88-7.86 (m, 1H),7.67 (s, 1H), 7.50 (s, 1H).

Synthesis of6-bromo-8-fluoro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione (7)

The synthesis of intermediate 7 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 0.24 g,34%; MS (ESI) m/z 275.07 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (d,J=7.44 Hz, 1H), 7.06 (s, 1H), 1.96 (s, 6H).

Synthesis of8-fluoro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 69)

The synthesis of compound 69 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 0.032 g,13%; MS (ESI) m/z 290.32 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s,1H), 9.61 (s, 1H), 8.83 (d, J=5.1 Hz, 1H), 8.79 (s, 1H), 8.45 (d, J=5.7Hz, 1H), 7.46 (d, J=5.6 Hz, 1H), 1.82 (s, 6H).

Example 70 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 70)

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 70)

The synthesis of compound 70 was carried out as described above usingthe general protocol of Procedure B. Yield: 22 mg; MS (ESI) m/z 361.33[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H), 8.90 (s, 1H), 8.63(s, 1H), 8.20 (s, 1H), 6.61 (s, 2H), 6.24 (s, 1H), 2.94 (t, J=11.36 Hz,2H), 1.65 (m, 5H), 1.51 (d, J=12.1 Hz, 2H), 1.21 (m, 1H).

Example 71 Synthesis of8-ethyl-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 71)

Synthesis of8-ethyl-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 71)

The synthesis of compound 71 was carried out as described above usingthe general protocol of Procedure G. Off white solid; Yield: 0.04 g,12%; MS (ESI) m/z 300.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.58 (s,1H), 9.40 (s, 1H), 8.78 (s, 1H), 8.67 (s, 1H), 8.38 (d, J=5.84 Hz, 1H),7.38 (d, J=5.36 Hz, 1H), 2.89 (q, J=7.76 Hz, 2H), 1.79 (s, 6H), 1.11 (t,J=7.36 Hz, 3H).

Example 72 Synthesis of8-chloro-3-methyl-3-(3-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 72)

Synthesis of6-bromo-8-chloro-3-methyl-3-(3-pyridyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yellow solid; Yield: 0.4 g, 57%; MS(ESI) m/z 354.02 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.4 (bs, 1H), 8.70(s, 1H), 8.57 (d, J=4 Hz, 1H), 8.31 (s, 1H), 7.82 (d, J=8.0 Hz, 1H),7.42-7.39 (m, 1H), 2.22 (s, 3H).

Synthesis of8-chloro-3-methyl-3-(3-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 72)

Procedure H: To a solution of6-bromo-8-chloro-3-methyl-3-(3-pyridyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(100 mg, 0.28 mmol) and pyrimidin-4-amine (30 mg, 0.31 mmol) in1,4-dioxane (12 mL) was added cesium carbonate (276 mg, 0.85 mmol). Thereaction was purged with argon for 15 min. XPhos (13 mg, 0.03 mmol),XantPhos (16 mg, 0.030 mmol), palladium acetate (6 mg, 0.030 mmol) andtris(dibenzylideneacetone)dipalladium(0) (26 mg, 0.030 mmol) were addedand purging was continued for another 10 min. The reaction was stirredat 100° C. for 16 h. After completion the reaction mass was diluted with10% methanol in dichloromethane and passed through celite pad. The crudefiltrate was then purified by flash column chromatography using 10%methanol in dichloromethane. The desired fractions were concentrated todryness under vacuum to obtain8-chloro-3-methyl-3-(3-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]pyridine-1,5-dioneas pale yellow solid. Yield: 0.059 g, 57%; MS (ESI) m/z 369.29 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H), 9.57 (s, 1H), 8.84 (d, J=6.2Hz, 1H), 8.75 (d, J=2.24 Hz, 1H), 8.56-8.55 (m, 1H), 7.82 (d, J=8.2 Hz,1H), 7.42-7.38 (m, 1H), 2.27 (s, 3H).

Example 73 Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(pyridin-4-yl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 73)

Synthesis of N-(6-((8-chloro-3-methyl-1,5-dioxo-3-(pyridin-4-yl)-1, 2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 73)

The synthesis of compound 73 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 0.030 g,16%; MS (ESI) m/z 352.34 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (brs,1H), 10.15 (s, 1H), 9.45 (brs, 1H), 8.76 (s, 1H), 8.58 (m, 3H), 7.90 (s,1H), 7.40 (brs, 2H), 2.21 (s, 3H), 2.05-1.95 (m, 1H), 0.90-0.75 (m, 4H).

Example 74 Synthesis of8-chloro-3-methyl-3-(2-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 74)

Synthesis of6-bromo-8-chloro-3-methyl-3-(pyridin-2-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 0.30 g, 42%; MS(ESI) m/z 354 [M+1]⁺.

Synthesis of8-chloro-3-methyl-3-(2-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 74)

The synthesis of compound 74 was carried out as described above usingthe general protocol of Procedure H. Off-white solid; Yield: 55 mg, 35%;¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (bs, 1H), 9.51 (bs, 1H), 8.84 (d,J=11.1 Hz, 2H), 8.52 (d, J=3.28 Hz, 1H), 8.40 (d, J=5.72 Hz, 1H),7.88-7.84 (m, 1H), 7.66 (d, J=8.12 Hz, 1H), 7.38-7.35 (m, 1H), 7.24 (d,J=5.84 Hz, 1H), 2.26 (s, 3H).

Example 75 Synthesis of8-chloro-3-methyl-3-(4-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 75)

Synthesis of6-bromo-8-chloro-3-methyl-3-(pyridin-4-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 0.36 g,51%; MS (ESI) m/z 354.02 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.4 (bs,1H), 8.57 (d, J=5.2 Hz, 2H), 8.33 (s, 1H), 7.40 (d, J=4.5 Hz, 2H), 2.17(s, 3H).

Synthesis of8-chloro-3-methyl-3-(4-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 75)

The synthesis of compound 75 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 59 mg, 57%;MS (ESI) m/z 369.29 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (bs, 1H),9.58 (s, 1H), 8.84 (d, J=2.88 Hz, 2H), 8.59 (d, J=5.64 Hz, 2H), 8.41 (d,J=5.88 Hz, 1H), 7.43 (d, J=5.76 Hz, 2H), 7.34 (d, J=5.76 Hz, 1H), 2.23(s, 3H).

Example 76 Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(pyridin-2-yl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 76)

Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(pyridin-2-yl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 76)

The synthesis of compound 76 was carried out as described above usingthe general protocol of Procedure H. Off-white solid; Yield: 15 mg, 8%;MS (ESI) m/z 452.35 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H),10.01 (s, 1H), 9.36 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 8.51 (d, J=4.32Hz, 1H), 7.85 (m, 2H), 7.63 (d, J=7.96, 1H), 7.37 (m, 1H), 2.27 (s, 3H),1.99 (m, 1H), 0.81 (m, 4H).

Example 77 Synthesis ofN-[6-[[8-chloro-3-methyl-1,5-dioxo-3-(3-pyridyl)-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 77)

Synthesis ofN-[6-[[8-chloro-3-methyl-1,5-dioxo-3-(3-pyridyl)-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 77)

The synthesis of compound 77 was carried out as described above usingthe general protocol of Procedure H. Pale yellow solid; Yield: 58 mg,15%; MS (ESI) m/z 452.36 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.99 (bs,1H), 10.12 (bs, 1H), 9.44 (s, 1H), 8.75 (s, 1H), 8.73 (d, J=2.0 Hz, 1H),8.58 (s, 1H), 8.56 (d, J=3.7 Hz, 1H), 7.90 (s, 1H), 7.42-7.38 (m, 1H),2.26 (s, 3H), 2.02-1.96 (m, 1H), 0.82-0.81 (m, 4H).

Example 78 Synthesis ofN-(6-((8′-chloro-2-fluoro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 78)

Synthesis of6′-bromo-8′-chloro-2-fluoro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 0.31 g; MS(ESI) m/z 348.8 [M+1]⁺.

Synthesis ofN-(6-((8′-chloro-2-fluoro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 78)

The synthesis of compound 78 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 50 mg,16%; MS (ESI) m/z 447.34 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,1H), 10.27 (s, 1H), 9.51 (s, 1H), 8.74 (s, 1H), 8.60 (s, 1H), 7.99 (s,1H), 5.64 (m, 1H), 2.95 (m, 1H), 2.1 (m, 1H), 2.02 (m, 1H), 1.72 (m,4H), 1.57 (m, 1H), 1.39 (m, 1H), 0.84 (d, J=5.12 Hz, 4H).

Example 79 Synthesis of3,3-dimethyl-6-(pyrimidin-4-ylamino)-8-vinyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 79)

Synthesis of3,3-dimethyl-6-(pyrimidin-4-ylamino)-8-vinyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 79)

The synthesis of compound 79 was carried out as described above usingthe general protocol of Procedure G. Pale yellow solid; Yield: 50 mg,17%; MS (ESI) m/z 298.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (s,1H), 9.47 (s, 1H), 9.14 (s, 1H), 8.81 (s, 1H), 8.40 (d, J=5.88 Hz, 1H),7.85 (dd, J=11.04 Hz, 1H), 7.40 (d, J=5.88 Hz, 1H), 5.75 (d, J=6.12 Hz,1H), 5.37 (d, J=11.24 Hz, 1H), 1.81 (s, 6H).

Example 80 Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(3-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 80)

Synthesis of6-bromo-8-chloro-3-methyl-3-(3-(trifluoromethyl)phenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 0.12 g,14%; MS (ESI) m/z 419 [M−1]⁻.

Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(3-(trifluoromethyl)phenyl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 80)

The synthesis of compound 80 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 16 mg, 11%;MS (ESI) m/z 519 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.58(s, 1H), 7.90 (s, 1H), 7.82 (s, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.68 (d,J=7.92 Hz, 1H), 7.62 (d, J=7.7 Hz, 1H), 2.27 (s, 3H), 1.98 (m, 1H), 0.81(m, 4H).

Example 81 Synthesis of8-methoxy-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 81)

Synthesis of6-bromo-8-methoxy-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Light brown solid; Yield: 0.5 g,41%; ¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (s, 1H), 6.75 (bs, 1H), 3.94 (s,3H), 1.93 (s, 6H).

Synthesis of8-methoxy-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 81)

The synthesis of compound 81 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.060 g, 15%;¹H NMR (400 MHz, DMSO-d₆) δ 9.50-9.41 (bs, 1H), 8.79 (s, 1H), 8.39 (d,J=4.0 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.13 (bs, 1H), 3.85 (s, 3H), 1.76(s, 6H).

Example 82 Synthesis of3,3-dimethyl-8-methylsulfanyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 82)

Synthesis of3,3-dimethyl-8-methylsulfanyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 82)

To a vial was added8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]pyridine-1,5-dione(1, 0.30 g, 0.98 mmol) in dimethylformamide (5 mL). Sodium thiomethoxide(0.14 g, 1.96 mmol) was added at room temperature, the vial was sealedand heated at 110° C. for 36 h. The reaction mixture was quenched withan aqueous ammonium chloride solution and extracted with 10% methanol indichloromethane. The organic layers were separated, combined, dried oversodium sulfate, filtered and concentrated it to dryness. Solids wereprecipitated by the addition of ice, filtered and dried. The solidmaterial was subjected to preparative HPLC to afford3,3-dimethyl-8-methylsulfanyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 82) as a yellow solid. Yield: 0.060 g, 19%; MS (ESI) m/z318.42 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 9.66 (s, 1H),8.92 (s, 1H), 8.84 (s, 1H), 8.45 (d, J=6.0 Hz, 1H), 7.47 (d, J=6.4 Hz,1H), 2.47 (s, 3H), 1.80 (s, 6H).

Example 83 Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(m-tolyl)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 83)

Synthesis of6-bromo-8-chloro-3-methyl-3-(m-tolyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 0.30 g,41%; MS (ESI) m/z 367 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H),8.29 (s, 1H), 7.26 (m, 1H), 7.16 (m, 3H), 2.30 (s, 3H), 2.18 (s, 3H).

Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-(m-tolyl)-1,2,3,5-tetrahydroimidazo-[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 83)

The synthesis of compound 83 was carried out as described above usingthe general protocol of Procedure H. Pale yellow solid; Yield: 60 mg,16%; MS (ESI) m/z 465.49 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s,1H), 10.04 (s, 1H), 9.40 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 7.88 (s,1H), 7.26 (m, 1H), 7.21 (m, 1H), 7.12 (m, 2H), 2.29 (s, 3H), 2.28 (s,3H) 1.99 (m, 1H), 0.82 (m, 4H).

Example 84 Synthesis ofN-[6-[(3-tert-butyl-8-chloro-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 84)

Synthesis of6-bromo-3-tert-butyl-8-chloro-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yellow solid; Yield: 150 mg, 28%;MS (ESI) m/z 332.8 [M+1]⁺.

Synthesis ofN-[6-[(3-tert-butyl-8-chloro-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 84)

The synthesis of compound 84 was carried out as described above usingthe general protocol of Procedure H. Brown solid; Yield: 0.060 g, 31%;MS (ESI) m/z 431.42 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (s, 1H),9.73 (s, 1H), 9.49 (s, 1H), 8.67 (s, 1H), 8.58 (s, 1H), 7.98 (s, 1H),2.02 (m, 1H), 1.92 (s, 1H), 0.98 (s, 9H), 0.83 (m, 4H).

Example 85 Synthesis ofN-[6-[[8-chloro-1,5-dioxo-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 85)

Synthesis of6-bromo-8-chloro-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 200 mg, 61%; ¹HNMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H), 8.34 (m, 1H), 6.57 (m, 1H).

Synthesis ofN-[6-[[8-chloro-1,5-dioxo-3-(trifluoromethyl)-2,3-dihydroimidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 85)

The synthesis of compound 85 was carried out as described above usingthe general protocol of Procedure B. Pale yellow solid; Yield: 0.035 g,14%; MS (ESI) m/z 429.33 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.95 (s,1H), 10.58 (s, 1H), 9.80 (s, 1H), 8.76 (s, 1H), 8.61 (s, 1H), 8.06 (s,1H), 6.61 (d, J=3.0 Hz, 1H), 2.02 (m, 1H), 0.84 (m, 4H).

Example 86 Synthesis ofN-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3, 3%azetidine]-6-yl) amino] pyrimidin-4-yl] cyclopropanecarboxamidehydrochloride (Cpd. No. 86)

Synthesis of tert-butyl6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-azetidine]-1′-carboxylate(3)

To a stirred solution of5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 1.0 g, 3.98 mmol)in 1,4-dioxane (12 mL) in a vial was added tert-butyl3-oxoazetidine-1-carboxylate (2, 2.72 g, 15.91 mmol) at roomtemperature. Concentrated sulfuric acid (0.39 g, 3.98 mmol) was thenadded dropwise. The vial was sealed and heated to 95° C. for 16 h. Thereaction mixture was concentrated, water (30 mL) was added and extractedwith ethyl acetate (2×30 mL). The organic layers were separated anddiscarded.

To a stirred solution of6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,3′-azetidine]-1,5-dione(0.41 g, 1.35 mmol) in 1,4-dioxane (30 mL) and water (25 mL, 1.35 mmol)was added di-tert-butyl dicarbonate (0.59 g, 2.71 mmol). The solutionwas cooled to 0° C. and 2 M aqueous sodium hydroxide solution was addeddropwise with stirring. The reaction mixture was stirred at roomtemperature overnight. After consumption of starting material asindicated by TLC, the mixture was extracted with 10% methanol indichloromethane (2×25 mL). The organic layers were separated and driedover magnesium sulfate, filtered and concentrated to dryness. The cruderesidue was then purified by flash column chromatography using neutralalumina with 2% methanol in dichloromethane. The desired fractions wereconcentrated to dryness under vacuum to afford tert-butyl6-bromo-8-chloro-1,5-dioxo-spiro [2H-imidazo[1,5-a]pyridine-3,3′-azetidine]-1′-carboxylate (3) as a yellow solid. Yield: 180 mg, 33%;MS (ESI) m/z 404.03 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H),8.28 (s, 1H), 4.88-4.68 (m, 2H), 3.97-3.89 (m, 2H), 1.42 (s, 9H).

Synthesis of tert-butyl8-chloro-6-[[6-(cyclopropanecarbonylamino)pyrimidin-4-yl]amino]-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-azetidine]-1′-carboxylate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.065 g; 29%;¹H NMR (400 MHz, DMSO-d₆) δ 10.93 (s, 1H), 10.46 (s, 1H), 9.63 (s, 1H),8.71 (s, 1H), 8.59 (s, 1H), 8.10 (s, 1H), 4.89-4.84 (m, 2H), 3.97-3.95(m, 2H), 2.02-2.0 (m, 1H), 1.42 (s, 9H), 0.79-0.75 (m, 4H).

Synthesis ofN-[6[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-azetidine]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamidehydrochloride (Cpd. No. 86)

The synthesis of compound 86 was carried out as described above usingthe general protocol of Procedure F. Light yellow solid; Yield: 0.03 g;61%; MS (ESI) m/z 402.34 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.04 (s,1H), 10.41 (s, 1H), 9.67 (s, 1H) 9.5 (bs, 1H), 8.79 (s, 1H), 8.74 (s,1H), 8.06 (s, 1H).

Example 87 Synthesis of 6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3-(3-fluorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 87)

Synthesis of 6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3-(3-fluorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 87)

Procedure I: In a vial containingN-[6-[[8-chloro-3-(3-fluorophenyl)-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(1, 0.23 g, 0.49 mmol) in tetrahydrofuran (5 mL), water (5 mL) andethanol (10 mL) at room temperature was added a concentrated aqueoussolution of potassium hydroxide (0.14 g, 2.45 mmol). Then reactionmixture was stirred for 16 h and was extracted with ethyl acetate (3×50mL). The organic layers were then separated and dried over sodiumsulfate, filtered and concentrated to dryness. The crude residue wassubjected to flash column chromatography with 2% methanol indichloromethane. The desired fractions were concentrated to dryness. Theresulting solid was washed with pentane and diethyl ether to afford theproduct as a yellow solid. Yield: 0.095 g, 48%; MS (ESI) m/z 401.40[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (brs, 1H), 8.86 (s, 1H), 8.68(s, 1H), 8.19 (s, 1H), 7.45-7.38 (m, 1H), 7.30 (d, J=8.8 Hz, 1H),7.23-7.15 (m, 2H), 6.58 (brs, 2H), 6.17 (s, 1H), 2.21 (s, 1H).

Example 88 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 88)

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 88)

The synthesis of compound 88 was carried out as described above usingthe general protocol of Procedure I. Light yellow solid; Yield: 0.14 g,68%; MS (ESI) m/z 321.34 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s,1H), 8.92 (s, 1H), 8.64 (s, 1H), 8.20 (s, 1H), 6.60 (s, 2H), 6.25 (s,1H), 1.79 (s, 6H).

Synthesis of 6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dionehydrogenchloride (hydrogenchloride salt of Cpd. No. 88)

To6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 88, 0.55 g, 1.71 mmol), in dichloromethane (10 mL), methanol(10 mL) a vial was added 4 M hydrogenchloride in 1,4-dioxane (10 mL).After stirring overnight at room temperature the reaction mixture wasconcentrated under vacuum, filtered, washed with methanol then diethylether and dried under vacuum to afford the product as a light yellowsolid. Yield: 0.61 g, 100%; MS (ESI) m/z 319.43 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 9.83 (s, 1H), 9.77 (s, 1H), 8.48 (s, 1H), 8.42 (s, 1H), 7.75(s, 2H), 6.49 (s, 1H), 1.79 (s, 6H).

Example 89 Synthesis of8-chloro-3-(3-chlorophenyl)-3-methyl-6-[[6-(methylamino)pyrimidin-4-yl]amino]-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 89)

Synthesis of8-chloro-3-(3-chlorophenyl)-3-methyl-6-[[6-(methylamino)pyrimidin-4-yl]amino]-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 89)

The synthesis of compound 89 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 50 mg, 16%; MS(ESI) m/z 431.32 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.89(s, 1H), 8.70 (s, 1H), 8.25 (s, 1H), 7.51 (s, 1H), 7.41 (m, 2H), 7.37(m, 1H), 7.05 (s, 1H), 6.24 (s, 1H), 2.68 (s, 3H), 2.19 (s, 3H).

Example 90 Synthesis of8-chloro-3-methyl-3-(6-methyl-2-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 90)

Synthesis of6-bromo-8-chloro-3-methyl-3-(6-methyl-2-pyridyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 0.41 g, 56%; MS(ESI) m/z 370 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (m, 1H), 8.30(s, 1H), 7.73 (m, 1H), 7.39 (m, 1H), 7.24 (m, 1H), 2.29 (s, 3H), 2.20(s, 3H).

Synthesis of8-chloro-3-methyl-3-(6-methyl-2-pyridyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 90)

The synthesis of compound 90 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.15 g,48%; MS (ESI) m/z 383.37 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s,1H), 9.48 (s, 1H), 8.83 (s, 1H), 8.81 (s, 1H), 8.39 (d, J=11.92 Hz, 1H),7.72 (t, J=7.78 Hz, 1H), 7.37 (m, 1H), 7.31 (m, 1H), 7.22 (m, 1H), 2.38(s, 3H), 2.25 (s, 3H).

Example 91 Synthesis ofN-[6-[[8-chloro-3-(3-fluorophenyl)-1,5-dioxo-2,3-dihydroimidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 91)

Synthesis of6-bromo-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

A mixture of 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1, 0.4 g,1.59 mmol), 3-fluorobenzaldehyde (2, 0.69 g, 5.57 mmol), acetonitrile(15 mL) and iron(III) chloride (1.81 g, 11.13 mmol) in a sealed tube washeated at 90° C. for 16 h. Once TLC showed consumption of the startingmaterial, the mixture was cooled and filtered through a celite bed. Thecelite was washed with acetonitrile and the filtrate was concentratedunder vacuum. The crude residue was subjected to flash columnchromatography eluting with 35% ethyl acetate in hexane. The desiredfractions were collected, concentrated and dried under high vacuum toafford6-bromo-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-c]pyridine-1,5-dione(3) as a yellow solid. Yield: 0.35 g, 61%; MS (ESI) m/z 357.20 [M+1]⁺.

Synthesis ofN-[6-[[8-chloro-3-(3-fluorophenyl)-1,5-dioxo-2,3-dihydroimidazo[1,5-a]-pyridin-6-yl]amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 91)

The synthesis of compound 91 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 46 mg, 18%. MS(ESI) m/z 455.33 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H),10.06 (s, 1H), 9.47 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 7.90 (s, 1H),7.44 (m, 1H), 7.41 (m, 1H), 7.24 (m, 2H), 6.62 (s, 1H), 2.00 (t, J=5.68Hz, 1H), 0.81 (m, 4H).

Example 92 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-3-(3-chlorophenyl)-3,8-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 92)

Synthesis of6-bromo-3-(3-chlorophenyl)-3,8-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Cream colored solid; Yield: 0.25 g,39%; MS (ESI) m/z 397.23 [M+1]⁺.

Synthesis of tert-butylN-[6-[[3-(3-chlorophenyl)-3,8-dimethyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl]amino]pyrimidin-4-yl]carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off-white semi-solid; Yield: 0.26g, 31%; MS (ESI) m/z 497.06[M+1]⁺.

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-3-(3-chlorophenyl)-3,8-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 92)

The synthesis of compound 92 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.077 g, 37%;MS (ESI) m/z 397.13 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.80 (s, 1H),8.57 (s, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.41 (m, 3H), 7.27 (d, J=6.3Hz, 1H), 6.50 (s, 2H), 6.10 (s, 1H), 2.47 (s, 3H), 2.20 (s, 3H).

Example 93 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3-(3-chlorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 93)

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3-(3-chlorophenyl)-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 93)

The synthesis of compound 93 was carried out as described above usingthe general protocol of Procedure I. Yellow solid; Yield: 0.17 g, 57%;MS (ESI) m/z 417.08 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.55 (s, 1H),8.15 (s, 1H), 7.39-7.35 (m, 3H), 6.08 (s, 1H), 2.17 (s, 3H).

Example 94 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(Cpd. No. 94)

Synthesis of6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 380 mg;60%; MS (ESI) m/z 315.06 [M−1]⁻.

Synthesis of tert-butylN-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-6-yl)amino]pyrimidin-4-yl]carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 0.30 g,71%. MS (ESI) m/z 447.03 [M+1]⁺.

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(Cpd. No. 94)

The synthesis of compound 94 was carried out as described above usingthe general protocol of Procedure F. Light yellow solid; Yield: 0.07 g,45%. MS (ESI) m/z 347.14 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s,1H), 9.15 (s, 1H), 8.60 (s, 1H), 8.26 (s, 1H), 6.85 (s, 2H), 6.30 (s,1H), 2.77 (s, 2H), 1.97 (s, 2H), 1.77 (m, 4H).

Example 95 Synthesis ofN-[6-[(8-chloro-1,1′,5-trioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-thietane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 95)

Synthesis of6-bromo-8-chloro-1′-oxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-thietane]-1,5-dione(2)

A 30% solution of hydrogen peroxide (0.53 g, 15.55 mmol) was addeddropwise to6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,3′-thietane]-1,5-dione(1, 1.0 g, 3.11 mmol) dissolved in acetone (15 mL). Acetic acid (18.66mg, 0.31 mmol) was added and the mixture was stirred at room temperaturefor 16 h. After TLC showed consumption of starting materials, thereaction mixture was concentrated under reduced pressure. The solidswere washed with diethyl ether and dichloromethane. The solid wasfiltered and dried under vacuum to afford 6-bromo-8-chloro-1′-oxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-thietane]-1,5-dione (2) as an off-whitesolid. Yield: 0.4 g, 38%; MS (ESI) m/z 335 [M+1]⁺; ¹H NMR (400 MHz,DMSO-d₆) δ 8.32 (s, 1H), 4.62 (d, J=12 Hz, 2H), 3.54 (d, J=16 Hz, 2H).

Synthesis ofN-[6[(8-chloro-1,1′,5-trioxo-spiro[2H-imidazo[1,5-a]pyridine-3,3′-thietane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 95)

The synthesis of compound 95 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 0.08 g,24%; MS (ESI) m/z 435.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.91 (bs,1H), 10.45-10.32 (m, 1H), 8.76 (bs, 1H), 8.59 (bs, 1H), 8.04 (bs, 1H),4.66-4.63 (m, 2H), 3.59-3.56 (m, 2H), 2.01 (bs, 1H), 0.84 (s, 4H).

Example 96 Synthesis of8-chloro-1′,1′-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,2′-cyclohexane]-1,5-dione(Cpd. No. 96)

Synthesis of6-bromo-8-chloro-1′,1′-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,2′-cyclohexane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Light brown solid; Yield: 0.41 g,57%; MS (ESI) m/z 360.8 [M+1]⁺.

Synthesis of8-chloro-1′,1′-dimethyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,2′-cyclohexane]-1,5-dione(Cpd. No. 96)

The synthesis of compound 96 was carried out as described above usingthe general protocol of Procedure B. Off white solids; Yield: 25 mg,10%; MS (ESI) m/z 374.19[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (bs,1H), 9.60 (s, 1H), 8.84 (s, 1H) 8.76 (s, 1H) 8.43 (d, J=4 Hz, 1H), 7.47(d, J=4 Hz, 1H), 3.61-3.50 (m, 1H), 1.75-1.36 (m, 7H), 1.25 (s, 3H),0.64 (s, 3H).

Example 97 Synthesis ofN-(6-((8-chloro-3-methyl-1,5-dioxo-3-phenyl-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(Cpd. No. 97)

Synthesis of6-bromo-8-chloro-3-methyl-3-phenyl-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Green solid; Yield: 525 mg, 75%; MS(ESI) m/z 353.21 [M+1]⁺.

Synthesis ofN-[6[(8-chloro-3-methyl-1,5-dioxo-3-phenyl-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(Cpd. No. 97)

The synthesis of compound 97 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 97 mg,15%. MS (ESI) m/z 451.13 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s,1H), 10.06 (s, 1H), 9.39 (s, 1H), 8.73 (s, 1H), 8.58 (s, 1H), 7.88 (s,1H), 7.39 (s, 5H), 2.24 (s, 3H), 1.99 (s, 1H), 0.81 (s, 4H).

Example 98 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dionehydrochloride (Cpd. No. 98)

Synthesis of6-bromo-8-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 1.8 g, 70%;MS (ESI) m/z 297.15 [M+1]⁺.

Synthesis ofN-[6[(8-methyl-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclopentane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. White solid; Yield: 1.30 g, 58%; MS(ESI) m/z 395.37 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 9.88(s, 1H), 9.20 (s, 1H), 8.51 (d, J=15.96 Hz, 2H), 7.86 (s, 1H), 2.81 (m,2H), 2.45 (m, 3H), 2.09 (m, 3H), 1.82 (m, 2H), 1.67 (m, 2H), 0.72 (m,4H).

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-methyl-spiro[2H-imidazo[1,5-a]-pyridine-3,1′-cyclopentane]-1,5-dionehydrochloride (Cpd. No. 98)

The synthesis of compound 98 was carried out as described above usingthe general protocol of Procedure I. White solid; Yield: 0.76 g, 87%; MS(ESI) m/z 327.49 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 9.75(s, 1H), 8.46 (s, 1H), 8.12 (s, 1H), 7.88 (s, 2H), 6.39 (s, 1H), 2.77(m, 2H), 2.41 (s, 3H), 1.96 (m, 2H), 1.83 (m, 2H), 1.70 (m, 2H).

Example 99 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-4′,4′-difluoro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 99)

Synthesis of6-bromo-8-chloro-4′,4′-difluoro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 5.9 g. 80%;MS (ESI) m/z 364.92 [M−1]⁻.

Synthesis ofN-[6[(8-chloro-4′,4′-difluoro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]pyrimidin-4-yl]cyclopropanecarboxamide(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Off-white solid; Yield: 4.71 g,63%; MS (ESI) m/z 465.38 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s,1H), 10.47 (s, 1H), 9.51 (s, 1H), 8.71 (s, 1H), 8.59 (s, 1H), 7.98 (s,1H), 3.32 (m, 2H), 2.24 (m, 4H), 2.02 (m, 1H), 1.71 (m, 2H), 0.64 (m,4H).

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-4′,4′-difluoro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure I. Light yellow solid; Yield: 0.35 g,41%; MS (ESI) m/z 397.33 [M+1]⁺.

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-4′,4′-difluoro-spiro[2H-imidazo-[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 99)

The synthesis of compound 99 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.66 g, 92%;MS (ESI) m/z 397.17 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H),9.87 (s, 1H), 8.51 (s, 1H), 8.43 (s, 1H), 7.89 (s, 2H), 6.52 (s, 1H),3.22 (m, 2H), 2.21 (m, 4H), 1.74 (d, J=12.12 Hz, 2H).

Example 100 Synthesis of8-chloro-6-((7-cyclopropylpyrido[4,3-d]pyrimidin-4-yl)amino)-3,3-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 100)

Synthesis of 4-amino-6-chloro-pyridine-3-carboxamide (2)

To a well stirred solution of 4,6-dichloropyridine-3-carboxamide (11.0g, 57.59 mmol) in 1,4-dioxane (20 mL) in steel bomb was added the liquidammonia (50 mL, 57.59 mmol). The steel bomb was closed and heated thereaction to 100° C. for 9 h. The progress of the displacement reactionwas monitored by TLC and LCMS. After completion the solid formed wasfiltered. The filtrate was also concentrated as it also contains 50%product. The combined solids were dried under vacuum to afford4-amino-6-chloro-pyridine-3-carboxamide (2) as a light brown solid.Yield: 10.6 g, crude, 47%; ¹H NMR (400 MHz, DMSO-d₆) δ 8.36 (s, 1H),7.97 (s, 1H), 7.50 (s, 1H), 7.37 (s, 1H), 6.65 (s, 1H).

Synthesis of 7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3)

4-Amino-6-chloro-pyridine-3-carboxamide (2, 4.5 g, 26.23 mmol) was addedto a pressure tube and triethylorthoformate (30 mL) was added. Thereaction vessel was sealed and heated to 140° C. for 11 h. After thecyclization was complete, the reaction mixture was concentrated underreduced pressure, and to the solid obtained was added diethyl ether. Thesolid was filtered, washed with diethyl ether and dried in vacuum toafford 7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3) as brown solid. MS(ESI) m/z 181.90 [M+1]⁺.

Synthesis of7-chloro-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one(4)

In a dried round bottom flask under N₂ atmosphere was added7-chloro-3H-pyrido[4,3-d]pyrimidin-4-one (3, 9.0 g, 49.56 mmol) todimethylformamide (50 mL). The solution was stirred at 0° C. and sodiumhydride (1.78 g, 74.35 mmol) was added portion-wise over 10 min. Theanionic suspension was stirred for 1 h at 0° C. followed by the additionof 2-(trimethylsilyl)ethoxymethyl chloride (12.4 g, 74.35 mmol) at 0° C.The reaction mixture was stirred at room temperature for 5 h. Afterconsumption of starting materials as indicated by TLC, the reactionmixture was quenched with ice. A solid precipitates. It was filtered andwashed with excess n-pentane. The solid was dried under vacuum to afford7-chloro-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one(4) as a brown solid. Yield: 9.1 g, 59%; ¹H NMR (400 MHz, DMSO-d₆) δ9.17 (s, 1H), 8.72 (s, 1H), 7.79 (s, 1H), 5.49 (s, 2H), 3.65 (t, J=16Hz, 2H), 0.90 (t, J=16 Hz, 2H), −0.03 (s, 9H).

Synthesis of7-cyclopropyl-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one(6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure G. Yellow liquid; Yield: 2.1 g, 52%;MS (ESI) m/z 319 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.57(s, 1H), 7.52 (s, 1H), 7.27 (s, 1H), 5.33 (s, 2H), 3.63-3.59 (m, 2H),2.32-2.26 (m, 1H) 1.07-1.05 (m, 4H), 0.89 (t, J=8.0 Hz, 1H), 0.04 (s,9H).

Synthesis of 7-cyclopropyl-3H-pyrido[4,3-d]pyrimidin-4-one (7)

To7-cyclopropyl-3-(2-trimethylsilylethoxymethyl)pyrido[4,3-d]pyrimidin-4-one(6, 2.0 g, 6.3 mmol) in dichloromethane (10 mL) at 0° C. was added a 20%trifluoroacteic acid solution in dichloromethane (10 mL, 6.3 mmol). Thereaction mixture was warmed to room temperature and stirred for 3 h.After complete deprotection as indicated by TLC the reaction mixture wasconcentrated, taken up in dichloromethane and concentrated. This processwas repeated 2-3 times. Tetrahydrofuran (20 mL) was added to the cruderesidue and cooled to 0° C. 3 M potassium hydroxide solution (10 mL, 6.3mmol) was added to the solution bringing the pH to 9-10. The suspensionwas stirred for 6-7 h. The reaction was concentrated, the residue wasdiluted with 10% methanol in dichloromethane and the organic layers werewashed with 10 mL water and 10 mL of a saturated brine solution. Theorganic layers were separated, dried over magnesium sulfate, filteredand concentration to dryness to afford 7-cyclopropyl-3H-pyrido[4,3-d]pyrimidin-4-one (7) as a brown solid. Yield: 1.00 g, 85%; MS(ESI) m/z 188.18 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.57 (bs, 1H),9.15 (s, 1H), 8.32 (s, 1H), 7.38 (s, 1H), 2.27 (bs, 1H), 1.03 (bs, 4H).

Synthesis of 7-cyclopropylpyrido[4, 3-d]pyrimidin-4-amine (8)

To 7-cyclopropyl-3H-pyrido[4,3-d]pyrimidin-4-one (7, 1.0 g, 5.34 mmol)in a round bottom flask under a nitrogen atmosphere was addedN,N-diisopropylethylamine (9.45 mL, 53.42 mmol) at 0° C. To this stirredmixture was slowly added phosphorus(V) oxychloride (7.48 mL, 80.13mmol). The reaction mixture was stirred at room temperature for 2-3 huntil a clear solution was obtained. The solution was concentrated underreduced pressure under inert conditions, taken up in excess toluene andreconcentrated. This process was repeated sev N,N-diisopropylethylamineeral times. The residue was dissolved in acetonitrile to it was added30% aqueous ammonia (30 mL). The mixture was heated to 120° C. for 16 hin sealed tube. The reaction mixture was diluted with 10% methanol indichloromethane and extracted from the aqueous ammonia. The organiclayers were separated, dried over Sodium sulfate, filtered andconcentrated to dryness. The crude residue was given Methanol washing.The solid obtained was dried to afford7-cyclopropylpyrido[4,3-d]pyrimidin-4-amine (8) as a brown solid. Yield:0.60 g, 60%; MS (ESI) m/z 375.8 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.34(s, 1H), 8.43 (s, 1H), 8.26-7.99 (m, 2H), 7.39 (s, 1H), 1.75 (s, 1H),1.01-0.84 (s, 4H).

Synthesis of8-chloro-6-[(7-cyclopropylpyrido[4,3-d]pyrimidin-4-yl)amino]-3,3-dimethyl-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 100)

The synthesis of compound 100 was carried out as described above usingthe general protocol of Procedure H. Pale yellow solid; Yield: 0.37 g,58%; MS (ESI) m/z 397.48 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s,1H), 8.85 (s, 1H), 8.75 (s, 1H), 7.58 (s, 1H), 2.32-2.29 (m, 1H), 1.82(s, 6H), 1.08-1.02 (m, 4H).

Example 101 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-3-(3-fluorophenyl)-3,8-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 101)

Synthesis of6-bromo-3-(3-fluorophenyl)-3,8-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yellow solid; Yield: 0.35 g, 46%;MS (ESI) m/z: 351.17 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H),8.08 (s, 1H), 7.42 (m, 1H), 7.21 (m, 2H), 7.13 (d, J=8.0 Hz, 1H), 2.43(s, 3H), 2.1 (s, 3H).

Synthesis of tert-butyl(6-((3-(3-fluorophenyl)-3,8-dimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.15 g, 34%;MS (ESI) m/z 481.47 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.0-9.80 (brs,2H), 9.01 (brs, 1H), 8.47 (s, 1H), 8.43 (s, 1H), 7.52 (s, 1H), 7.38 (m,1H), 7.10-7.22 (m, 3H), 2.43 (s, 3H), 2.16 (s, 3H), 1.46 (s, 9H).

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-3-(3-fluorophenyl)-3,8-dimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 101)

The synthesis of compound 101 was carried out as described above usingthe general protocol of Procedure F. Off-white solid; Yield: 0.09 g,76%; MS (ESI) m/z 381.50 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s,1H), 8.60 (s, 1H), 8.45 (s, 1H), 8.17 (s, 1H), 7.42 (m, 1H), 7.25-7.10(m, 3H), 6.54 (brs, 2H), 6.10 (s, 1H), 2.47 (s, 3H), 2.20 (s, 3H).

Example 102 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dionehydrochloride (Cpd. No. 102)

Synthesis ofN-(6-((3,3,8-trimethyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.85 g, 50%;MS (ESI) m/z 369.0 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H),9.52 (s, 1H), 9.16 (s, 1H), 8.53 (s, 1H), 8.47 (s, 1H), 7.86 (s, 1H),5.75 (s, 1H), 2.42 (s, 3H), 2.02 (m, 1H), 1.77 (s, 6H), 0.88-0.80 (m,4H).

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure I. Yellow solid; Yield: 0.55 g, 80%;MS (ESI) m/z 301.29 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H),8.61 (s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 6.53 (brs, 2H), 6.16 (s, 1H),2.40 (s, 3H), 1.77 (s, 6H).

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-3,3,8-trimethyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dionehydrochloride (Cpd. No. 102)

The synthesis of compound 102 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.60 g, 97%;MS (ESI) m/z 301.25 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H),9.67 (s, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 7.95-7.70 (brs, 2H), 6.39 (s,1H), 2.41 (s, 3H), 1.77 (s, 6H).

Example 103 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-4′,4′-difluoro-8-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 103)

Synthesis of6-bromo-4′,4′-difluoro-8-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 1.2 g, 53%;MS (ESI) m/z 346.99 [M+1]⁺.

Synthesis of tert-butylN-[6-[(4′,4′-difluoro-8-methyl-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]pyrimidin-4-yl]carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.8 g, 58%; MS(ESI) m/z 477.48 [M+1]⁺.

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-4′,4′-difluoro-8-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 103)

The synthesis of compound 103 was carried out as described above usingthe general protocol of Procedure D. Yellow solid; Yield: 0.75 g, 97%;MS (ESI) m/z 377.40 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H),9.73 (s, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.87 (brs, 2H), 6.40 (s, 1H),3.30 (m, 2H), 2.43 (s, 3H), 2.32-2.29 (m, 1H), 2.20-2.10 (m, 3H), 1.65(m, 2H).

Example 104 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (Cpd. No. 104)

Synthesis of tert-butyl8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.8 g, 52%; MS(ESI) m/z 447 [M+1]⁺.

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (Cpd. No. 104)

The synthesis of compound 104 was carried out as described above usingthe general protocol of Procedure F. Pale yellow solid; Yield: 0.6 g,93%; MS (ESI) m/z 347.37 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.69 (s,1H), 10.52 (brs, 1H), 9.46 (m, 1H), 8.72 (s, 1H), 8.52 (d, J=6.0 Hz,1H), 7.57 (d, J=5.6 Hz, 1H), 3.50-3.45 (m, 2H), 3.36-3.12 (m, 4H),1.91-1.86 (m, 2H).

Example 105 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-3-tert-butyl-8-chloro-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dionehydrochloride (Cpd. No. 105)

Synthesis of tert-butylN-[6-[(3-tert-butyl-8-chloro-3-methyl-1,5-dioxo-2H-imidazo[1,5-a]pyridin-6-yl)amino]pyrimidin-4-yl]carbamate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.21 g, 50%;MS (ESI) m/z 431.39 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H),9.73 (s, 1H), 9.50 (s, 1H), 8.57 (s, 1H), 8.51 (s, 1H), 7.77 (s, 1H),1.92 (s, 3H), 1.48 (s, 9H), 0.99 (s, 9H).

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-3-tert-butyl-8-chloro-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dionehydrochloride (Cpd. No. 105)

The synthesis of compound 105 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.08 g, 54%;MS (ESI) m/z 363.46 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 2H),8.51 (s, 1H), 8.40 (s, 1H), 7.89 (brs, 2H), 6.54 (s, 1H), 1.92 (s, 3H),0.99 (s, 9H).

Example 106 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionedihydrochloride (Cpd. No. 106)

Synthesis of tert-butyl6-bromo-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure E. Off-white solid; Yield: 1.7 g, 43%;MS (ESI) m/z 409.9 [M−1]⁻; ¹H NMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H),8.04 (s, 1H), 4.03 (brs, 2H), 3.56 (brs, 1H), 3.11 (brs, 4H), 2.23 (s,3H), 1.42 (s, 9H).

Synthesis of tert-butyl6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 1.6 g, 60%; MS(ESI) m/z 542.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (brs, 1H),9.98 (s, 1H), 9.19 (s, 1H), 8.50-8.45 (m, 2H), 7.66 (s, 1H), 4.05 (brs,1H), 3.32 (m, 2H), 2.24 (s, 3H), 1.48 (s, 9H), 1.43 (s, 9H).

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]-pyridine-3,4′-piperidine]-1,5-dionedihydrochloride (Cpd. No. 106)

The synthesis of compound 106 was carried out as described above usingthe general protocol of Procedure F. Pale yellow solid; Yield: 1.02 g,83%; MS (ESI) m/z 342.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (brs,1H), 9.55 (brs, 1H), 9.24 (brs, 1H), 8.78 (brs, 1H), 8.41 (s, 1H), 8.16(s, 1H), 7.58 (brs, 2H), 6.37 (s, 1H), 3.48-3.40 (m, 2H), 3.40-3.28 (m,2H), 3.20-3.10 (m, 1H), 2.38 (s, 3H), 1.73 (m, 2H).

Example 107 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 107)

Synthesis of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 2.4 g, 71%;MS (ESI) m/z 311.18 [M+1]⁺.

Synthesis of tert-butyl(6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off-white solid; Yield: 2.10 g,30%.

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 107)

The synthesis of compound 107 was carried out as described above usingthe general protocol of Procedure F. Off-white solid; Yield: 0.55 g,64%; MS (ESI) m/z 341.50; [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s,1H), 9.68 (s, 1H), 8.45 (s, 1H), 8.10 (s, 1H), 7.88 (brs, 2H), 6.39 (s,1H), 3.00-2.90 (m, 2H), 2.42 (s, 3H), 1.80-1.60 (m, 5H), 1.42 (d, J=12Hz, 2H), 1.25-1.12 (m, 1H).

Example 108 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionedihydrochloride (Cpd. No. 108)

Synthesis of tert-butyl6-[[6-(tert-butoxycarbonylamino)pyrimidin-4-yl]amino]-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Off-white solid; Yield: 1.6 g, 54%;MS (ESI) m/z 562.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H),10.05 (s, 1H), 9.49 (s, 1H), 8.72 (s, 1H), 8.51 (s, 1H), 7.78 (s, 1H),4.09 (brs, 1H), 3.33 (m, 4H), 1.74 (brs, 1H), 1.48 (s, 9H), 1.43 (s,9H).

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionedihydrochloride (Cpd. No. 108)

The synthesis of compound 108 was carried out as described above usingthe general protocol of Procedure F. Pale yellow solid; Yield: 0.8 g,96%; MS (ESI) m/z 362.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (s,1H), 9.82 (s, 1H), 9.49-9.46 (m, 1H), 9.01-8.98 (m, 1H), 8.51 (s, 1H),8.40 (s, 1H), 7.91 (brs, 2H), 6.54 (s, 1H), 3.54-3.47 (m, 2H), 3.38-3.18(m, 4H), 1.88-1.85 (m, 2H).

Example 109 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 109)

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Off-white solid; Yield: 0.8 g, 64%;MS (ESI) m/z 346.04 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H),9.61 (s, 1H), 8.84 (s, 1H), 8.43 (d, J=6.4 Hz, 1H), 7.45 (d, J=6.4 Hz,1H), 2.9 (t, J=9.2 Hz, 2H), 1.65-1.54 (m, 6H), 1.25-1.23 (m, 2H).

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 109)

The synthesis of compound 109 was carried out as described above usingthe general protocol of Procedure F. Light yellow solid; Yield: 0.6 g,77%; MS (ESI) m/z 346.04 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s,1H), 10.23 (s, 1H), 9.0 (s, 1H), 8.71 (s, 1H), 8.48 (d, J=6.4 Hz, 1H),7.52 (d, J=6.4 Hz, 1H), 2.9 (t, J=9.2 Hz, 2H), 1.78-1.54 (m, 6H),1.23-1.27 (m, 2H).

Example 110 Synthesis of8-chloro-4′,4′-difluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 110)

Synthesis of8-chloro-4′,4′-difluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.85 g, 35%;MS (ESI) m/z 382.36 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H),9.68 (s, 1H), 8.80-8.84 (m, 2H), 8.44 (d, J=6.8 Hz, 1H), 7.44 (d,J=6.4.0 Hz, 1H), 3.34-3.17 (m, 2H), 2.32-2.17 (m, 4H), 1.76-1.72 (m,2H).

Synthesis of8-chloro-4′,4′-difluoro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 110)

The synthesis of compound 110 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.81 g, 87%;MS (ESI) m/z 382.4 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (s, 1H),10.45 (s, 1H), 9.05 (s, 1H), 8.71 (s, 1H), 8.52 (d, J=6.8 Hz, 1H), 7.56(d, J=6.4 Hz, 1H), 3.30-3.20 (m, 2H), 2.35-2.15 (m, 4H), 1.80-1.72 (m,2H).

Example 111 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-6′,8-dichloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-indane]-1,5-dionehydrochloride (Cpd. No. 111)

Synthesis of6-bromo-6′,8-dichloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-indane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off-white solid; Yield: 0.52 g,35%; MS (ESI) m/z: 399.23 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s,1H), 8.28 (s, 1H), 7.39 (m, 3H), 3.23 (m, 1H), 3.08 (m, 2H), 2.43 (m,1H).

Synthesis of tert-butylN-[6-[(6′,8-dichloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-indane]-6-yl)amino]pyrimidin-4-yl]carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off-white solid; Yield: 0.38 g,56%; MS (ESI) m/z 529.2 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s,1H), 9.99 (s, 1H), 9.42 (s, 1H), 8.72 (s, 1H), 8.50 (s, 1H), 7.65 (s,1H), 7.37 (m, 3H), 3.10 (m, 2H), 3.01 (m, 2H), 1.45 (s, 9H).

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-6′,8-dichloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-indane]-1,5-dionehydrochloride (Cpd. No. 111)

The synthesis of compound 111 was carried out as described above usingthe general protocol of Procedure F. Pale yellow solid; Yield: 0.17 g,55%; MS (ESI) m/z 429.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.18 (s,1H), 9.78 (s, 1H), 8.52 (s, 1H), 8.44 (s, 1H), 7.91 (brs, 2H), 7.38 (m,3H), 6.42 (s, 1H), 3.30 (m, 1H), 3.21 (m, 1H), 2.96 (m, 1H), 2.47 (m,1H).

Example 112 Synthesis of8-chloro-6-[(5-fluoropyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 112)

Synthesis of8-chloro-6-[(5-fluoropyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 112)

The synthesis of compound 112 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.14 g, 43%;MS (ESI) m/z 364.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H),8.73 (s, 1H), 8.62 (s, 2H), 8.54 (s, 1H), 2.95-2.87 (m, 2H), 1.80-1.54(m, 7H), 1.30-1.18 (m, 1H).

Example 113 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,2′-indane]-1,1′,5-trione(Cpd. No. 113)

Synthesis of6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,2′-indane]-1,1′,5-trione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 0.12 g, 28%; MS(ESI) m/z 378.94 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 8.40(s, 1H), 7.88-7.81 (m, 2H), 7.70 (d, J 7.32, 1H), 7.57 (t, J=7.36, 1H),4.12 (d, J=18.32, 1H), 3.43 (d, J=18.08, 1H).

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,2′-indane]-1,1′,5-trione(Cpd. No. 113)

The synthesis of compound 113 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.065 g, 26%;MS (ESI) m/z 394.06 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (brs, 1H),9.64 (s, 1H), 8.85 (s, 2H), 8.41 (d, J=5.68 Hz, 1H), 7.86-7.80 (m, 2H),7.69 (d, J=7.44 Hz, 1H), 7.55 (t, J=7.44, 1H), 7.30 (d, J=5.92 Hz, 1H),4.15 (d, J=18.2 Hz, 1H), 3.50 (d. J=18.44 Hz, 1H).

Example 114 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6′-fluoro-2′,3′-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-indene]-1,5-dionehydrochloride (Cpd. No. 114)

Synthesis of6-bromo-8-chloro-6′-fluoro-2′,3′-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-indene]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 0.46 g, 32%; MS(ESI) m/z 381.19 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H),8.31-8.28 (s, 1H), 7.37-7.34 (m, 1H), 7.20-7.16 (m, 2H), 3.22 (m, 1H),3.06-2.97 (m, 2H), 2.42-2.35 (m, 1H).

Synthesis of tert-butyl(6-((8-chloro-6′-fluoro-1,5-dioxo-1,2′,3′,5-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-inden]-6-yl)amino)pyrimidin-4-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 320 mg,53%; MS (ESI) m/z 513.35 [M+1]⁺.

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6′-fluoro-2′,3′-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-indene]-1,5-dionehydrochloride (Cpd. No. 114)

The synthesis of compound 114 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.089 g, 37%;MS (ESI) m/z 413.32 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H),9.72 (s, 1H), 8.49-8.46 (d, 2H), 7.86-7.69 (b s, 2H), 7.36 (m, 1H), 7.19(m, 1H), 7.11 (m, 1H), 6.41 (s, 1H), 3.31-3.35 (m, 2H), 3.17-2.96 (m,2H).

Example 115 Synthesis of8-chloro-6-[(5-chloropyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 115)

Synthesis of8-chloro-6-[(5-chloropyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 115)

The synthesis of compound 115 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 75 mg, 13%; MS(ESI) m/z 380.23 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 8.85(s, 1H), 8.80 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 2.93-2.88 (m, 2H),1.77-1.74 (m, 2H), 1.65-1.61 (m, 3H), 1.57-1.57 (m, 2H), 1.04-1.02 (m,1H).

Example 116 Synthesis of8-chloro-6-[(6-methylpyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 116)

Synthesis of8-chloro-6-[(6-methylpyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 116)

The synthesis of compound 116 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 190 mg, 58%;MS (ESI) m/z 359.81 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H),10.08 (s, 1H), 9.41 (s, 1H), 8.76 (s, 1H), 8.71 (s, 1H), 7.27 (s, 1H),2.98-2.91 (m, 2H), 2.33 (s, 3H), 1.77-1.74 (m, 2H), 1.67-1.58 (m, 3H),1.55-1.52 (m, 2H) 1.26-1.19 (m, 1H).

Example 117 Synthesis of6′-((7H-purin-6-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 117)

Synthesis ofN-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purin-6-yl)isobutyramide (2)

To a stirred solution of 2-methyl-N-(7H-purin-6-yl)propanamide (1, 5 g,24.36 mmol) in dimethylformamide (20 mL), sodium hydride (0.88 g, 36.55mmol) was added portion wise in 10 minutes at 0° C. The above suspensionwas stirred for 10 minutes at 0° C. followed by addition of2-(trimethylsilyl)ethoxymethyl chloride (4.87 g, 29.24 mmol) slowly at0° C. under nitrogen atmosphere. The reaction was stirred at roomtemperature for 16 h. After completion of the reaction, the mixture wasquenched with saturated aqueous solution of ammonium chloride andproduct was extracted with dichloromethane (2×50 mL). The organics werethen separated, dried (magnesium sulfate) and concentrated to drynessunder vacuum and the crude was purified by flash chromatography elutingwith 2% methanol in dichloromethane. Concentration of the desiredfractions afford2-methyl-N-[7-(2-trimethylsilylethoxymethyl)purin-6-yl]propanamide (2)as white solid. Yield: 2 g, 24%.

Synthesis of 7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purin-6-aminehydrochloride (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure I. White solid; Yield: 3.0 g, 73%; MS(ESI) m/z 266.31[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.26 (s, 1H), 8.16(s, 1H), 7.26 (brs, 2H), 5.50 (s, 2H), 3.52 (t, J=1.56 Hz, 2H), 0.835(t, J=1.56 Hz, 2H), 0.088 (s, 9H).

Synthesis of8′-chloro-6′-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-purin-6-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.10 g, 26%;MS (ESI) m/z 516.44 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H),9.07 (s, 1H), 9.03 (s, 1H), 8.71 (s, 1H), 8.58 (s, 1H), 5.74 (s, 2H),3.61 (t, J=1.6 Hz, 2H), 0.852 (t, J=1.64 Hz, 2H), 0.081 (s, 9H).

Synthesis of6′-((7H-purin-6-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 117)

8-Chloro-6-[[7-(2-trimethylsilylethoxy)purin-6-yl]amino]spiro[2H-imidazo[1,5-c]pyridine-3,1′-cyclohexane]-1,5-dione(5, 0.6 g, 1.2 mmol) was dissolved in dichloromethane (10 mL) in a flaskand trifluoroacetic acid (1.36 g, 11.95 mmol) was added dropwise andstirred the mixture at room temperature overnight. After completion,evaporated the solvent under reduced pressure and the crude was basifiedby saturated aqueous solution of sodium bicarbonate to pH 8 andextracted with dichloromethane (2×50 mL). The organic layer was driedover anhydrous. Sodium sulfate and concentrated to afford crude. Thecrude was purified by flash column chromatography eluting with 2.5%methanol in dichloromethane. The desired fractions were concentrated todryness under vacuum to afford8-chloro-6-(7H-purin-6-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 117) as a yellow solid. Yield: 0.06 g, 13%; MS (ESI) m/z386.39 [M+1]⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ 10.43 (m, 1H), 10.37 (s,1H), 8.88 (s, 1H), 8.64 (s, 1H), 8.43 (s, 1H), 2.94 (t, J=2.32 Hz, 2H),1.77 (m, 2H), 1.63 (m, 3H), 1.57 (d, J=12.8 Hz, 2H), 1.23 (m, 1H).

Example 118 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-1,5-dioxo-imidazo[1,5-a]pyridine-2-carbonitrile(Cpd. No. 118)

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure I. Yellow solid; Yield: 0.36 g, 71%;MS (ESI) m/z 341.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H),8.62 (s, 1H), 8.57 (d, J=7.64, 1H), 8.15 (s, 1H), 6.80 (d, J=7.68, 1H),6.51 (s, 2H), 6.16 (s, 1H), 3.4 (m, 1H), 1.82 (s, 3H), 1.63-1.41 (m,5H), 1.1 (m, 1H), 0.87-0.75 (m, 2H).

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-1,5-dioxo-imidazo[1,5-a]pyridine-2-carbonitrile(Cpd. No. 118)

In a 2-neck round bottom flask6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-2H-imidazo[1,5-a]pyridine-1,5-dione(2, 0.28 g, 0.82 mmol) was taken in dry tetrahydrofuran (15 mL). Thereaction mixture was cooled to 0° C. and sodium hydride (164 mg, 4.11mmol) was added in portions. After stirring for 10 min at roomtemperature, cyanogen bromide (436 mg, 4.11 mmol) was added and theresulting reaction mixture was stirred at room temperature for 20 h. Thereaction mixture was quenched with aqueous ammonium chloride solutionand then concentrated to get the crude mass. This crude was purified byflash chromatography eluting with 2% methanol in dichloromethane. Thecompound was washed with pentane and dried under vacuum to afford6-[(6-aminopyrimidin-4-yl)amino]-3-cyclopentyl-3-methyl-1,5-dioxo-imidazo[1,5-a]pyridine-2-carbonitrile(Cpd. No. 118) as yellow solid. Yield: 0.018 g, 6%; MS (ESI) m/z 366.16[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.71 (d, J=7.84, 1H),8.19 (s, 1H), 7.28 (d, J=7.96, 1H), 6.65 (s, 2H), 6.29 (s, 1H),3.49-3.43 (m, 1H), 2.21 (s, 3H), 1.94 (m, 1H), 1.7-1.58 (m, 4H), 1.48(m, 1H), 1.23 (m, 1H), 1.06-1.02 (m, 1H).

Example 119 Synthesis of 6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 119)

Synthesis of6-bromo-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

To a suspension of 5-bromo-3-chloro-6-oxo-1H-pyridine-2-carboxamide (1,0.5 g, 1.99 mmol) in acetonitrile (15 mL), 3-fluorobenzaldehyde (0.86 g,6.96 mmol) and ferric chloride (2.25 g, 13.92 mmol) were added in avial. The vial was sealed and heated the reaction mass to 85° C. for 16h. After completion, the reaction mass was cooled to room temperature,filtered through celite bed, washed with 5% methanol in dichloromethanefollowed by concentration to get crude. The crude was then purified bycolumn chromatography eluting with 5% methanol in dichloromethane toafford 8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione as white solid. Yield: 0.45 g,63%; MS (ESI) m/z 256.17 [M+1]⁺.

Synthesis of tert-butyl(6-((8-chloro-3-(3-fluorophenyl)-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.15 g, 33%;MS (ESI) m/z 487.43 [M+1]⁺.

Synthesis of 6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-3-(3-fluorophenyl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 119)

The synthesis of compound 119 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 0.012 g,10%; MS (ESI) m/z 387.29 [M+]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s,1H), 8.90 (s, 1H), 8.70 (s, 1H), 8.20 (s, 1H), 7.43 (m, 1H), 7.33 (m,1H), 7.19 (s, 2H), 6.61 (s, 1H), 6.58 (s, 2H), 6.17 (s, 1H).

Example 120 Synthesis of8′-chloro-2,2-dimethyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclobutane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 120)

Synthesis6′-bromo-8′-chloro-2,2-dimethyl-2′H-spiro[cyclobutane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 0.51 g;64%; MS (ESI) m/z 331.59 [M+1]⁺.

Synthesis8′-chloro-2,2-dimethyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclobutane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 120)

The synthesis of compound 120 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 0.12 g,39%; MS (ESI) m/z 346.80 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s,1H), 9.75 (s, 1H), 8.85 (s, 1H), 8.80 (s, 1H), 8.84 (d, J=16.88 Hz, 1H),7.48 (d, J=5.72 Hz, 2H), 3.13-3.08 (m, J=9.44 Hz, 1H), 2.66-2.59 (m,J=9.64 Hz, 1H), 1.20 (s, 3H), 0.98 (s, 3H).

Example 121 Synthesis of 6′-((6-Aminopyrimidin-4-yl)amino)-8′-chloro-2,2-dimethyl-2′H-spiro[cyclobutane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 121)

Synthesis of tert-butyl(6-((8′-chloro-2,2-dimethyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclobutane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.31 g,crude; MS (ESI) m/z 461.90 [M+1]⁺.

Synthesis of 6′-((6-aminopyrimidin-4-yl)amino)-8′-chloro-2,2-dimethyl-2′H-spiro[cyclobutane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 121)

The synthesis of compound 121 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.070 g, 30%;MS (ESI) m/z 361.92 [M+1]⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ 9.94 (s, 1H),9.07 (s, 1H), 8.67 (s, 1H), 8.21 (s, 1H), 6.61 (s, 2H), 3.12-3.05 (m,J=2.48 Hz, 1H), 2.66-2.58 (m, J=5.4 Hz, 1H), 1.55-1.50 (m, J=3.0 Hz,1H), 1.19 (s, 3H), 0.96 (s, 3H).

Example 122 Synthesis of6-[(6-amino-5-chloro-pyrimidin-4-yl)amino]-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 122)

Synthesis tert-butylN-tert-butoxycarbonyl-N-(5,6-dichloropyrimidin-4-yl)carbamate (2)

Procedure J: To a stirred solution of 5, 6-dichloropyrimidin-4-amine (1,3.0 g, 18.29 mmol) in tetrahydrofuran (30 mL), 4-dimethylaminopyridine(0.16 g, 1.31 mmol) and di-tert-butyl dicarbonate (8.77 g, 40.2 mmol)were added at room temperature. The reaction mass was stirred at roomtemperature for overnight. After completion, distilled out the solvent.The above residue was diluted with water and extracted with ethylacetate (2×50 mL). The organics were then separated and dried (magnesiumsulfate) and concentrated to dryness under vacuum to afford ethyltert-butyl N-tert-butoxycarbonyl-N-(5,6-dichloropyrimidin-4-yl)carbamate(2) as white solid. Yield: 3.1 g, 47%; MS (ESI) m/z 364.3 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 1.40 (s, 18H).

Synthesis of tert-butylN-tert-butoxycarbonyl-N-[5-chloro-6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]pyrimidin-4-yl]carbamate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.10 g, 26%;MS (ESI) m/z 595.45 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s, 1H),8.99 (s, 1H), 8.95 (s, 1H), 8.66 (s, 1H), 2.90 (m, 2H), 1.65 (m, 7H),1.46 (s, 18H), 1.20 (m, 1H).

Synthesis of6-[(6-amino-5-chloro-pyrimidin-4-yl)amino]-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 122)

The synthesis of compound 122 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.059 g, 81%;MS (ESI) m/z 395.35 [M+1]⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ 10.35 (s, 1H),8.62 (s, 1H), 8.55 (s, 1H), 8.23 (s, 2H), 7.27 (s, 1H), 2.91 (t, J=2.28,2H), 1.75 (m, 2H), 1.63 (m, 3H), 1.53 (d, J=12.8 Hz, 2H), 1.23 (m, 1H).

Example 123 Synthesis of6′-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 123)

Synthesis of6′-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.60 g, crude;MS (ESI) m/z 385.19 [M+1]⁺

Synthesis of6′-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 123)

To a stirred solution of8-chloro-6-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(3, 0.6 g, 1.56 mmol) in methanol (6 mL) 4 M hydrogenchloride in dioxane(4 mL) was added under cooling and stirred the reaction mixture at roomtemperature for overnight. After completion filtered the reaction massusing sintered funnel and washed with ethanol (10 mL). The solidobtained was dried under high vacuum to afford8-chloro-6-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 123) as light yellow solid; Yield: 0.21 g, 32%;MS (ESI) m/z 385.31 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.24 (s, 1H),10.39 (s, 1H), 9.12 (s, 1H), 8.75 (s, 1H), 8.50 (s, 1H), 7.43 (s, 1H),6.88 (s, 1H), 2.95 (t, J=11.14 Hz, 2H), 1.76 (m, 2H), 1.62 (m, 5H), 1.22(m, 1H).

Example 124 Synthesis of8-chloro-3,3-dimethyl-6-(pyrido[4,3-d]pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 124)

Synthesis of 8-chloro-3, 3-dimethyl-6-(pyrido[4,3-d]pyrimidin-4-ylamino)-2, 3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 124)

The synthesis of compound 124 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.060 g, 16%;MS (ESI) m/z 357.77 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 2H),9.69 (s, 1H), 8.96 (s, 1H), 8.90-8.86 (d, 1H), 8.87 (s, 1H), 7.73 (d,1H), 1.84 (s, 6H).

Example 125 Synthesis of8′-chloro-6′-((2-methylpyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 125)

Synthesis of8′-chloro-6′-((2-methylpyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 125)

The synthesis of compound 125 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.16 g,45%; MS (ESI) m/z 360.38 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s,1H), 10.47 (s, 1H), 8.67 (s, 1H), 8.45 (m, 1H), 7.44 (d, J=4.8 Hz, 1H),2.91 (t, J=11.74 Hz, 2H), 2.65 (s, 3H), 1.76 (m, 2H), 1.65 (m, 3H), 1.56(m, 2H), 1.19 (m, 1H).

Example 126 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione(Cpd. No. 126)

Synthesis of6-bromo-8-chloro-1′,4′-ditosyl-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 1.7 g, 43%; MS(ESI) m/z 442.31 [M+1]⁺.

Synthesis of6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione(4)

To a stirred solution of hydrogenbromide (1.43 g, 15.24 mmol) in aceticacid in 1,4-dioxane (30 mL),6-bromo-8-chloro-1′,4′-ditosyl-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione(1 g, 1.52 mmol) was added at room temperature. The vial was sealed andheated the reaction mass to 100° C. for 16 h. After completion, solventwas removed under reduced pressure and crude was triturated withdichloromethane to afford6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione(4) as brown solid. Yield: 0.5 g, 94%; MS (ESI) m/z 362.28 [M+1]⁺.

Synthesis of di-tert-butyl6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1′,4′-dicarboxylate(5)

To a stirred solution of di-tert-butyl dicarbonate (0.94 g, 4.32 mmol)in dichloromethane (30 mL) in a vial at room temperature,6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione(4, 0.5 g, 1.44 mmol) and triethylamine (0.73 g, 7.19 mmol) were added.The vial was sealed and stirred the reaction mass at room temperaturefor 16 h. After completion, the solvent was removed and the crude wastriturated with hexane to afford di-tert-butyl6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1′,4′-dicarboxylate(5) as yellow solid. Yield: 0.45 g, 57%; MS (ESI) m/z 547.13 [M+1]⁺.

Synthesis of di-tert-butyl6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1′,4′-dicarboxylate(7)

The synthesis of intermediate 7 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.41 g, 74%;MS (ESI) m/z 677.32 [M+1]⁺.

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,6′-[1,4]diazepane]-1,5-dione(Cpd. No. 126)

The synthesis of compound 126 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 0.04 g,18%; MS (ESI) m/z 377.32 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (s,1H), 8.98 (s, 1H), 8.66 (s, 1H), 8.20 (s, 1H), 6.61 (s 2H), 6.25 (s,1H), 3.61-3.58 (m, 2H), 2.95-2.91 (m, 2H), 2.82 (s, 4H), 2.66-2.61 (m,2H).

Example 127 Synthesis of6′-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 127)

Synthesis of6′-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 127)

The synthesis of compound 127 was carried out as described above usingthe general protocol of Procedure B. Yield: 0.037 g, 6%; MS (ESI) m/z386.36 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s, 1H), 9.55 (s, 1H),8.91 (s, 1H), 8.61 (s, 2H), 2.97 (m, 2H), 1.76-1.56 (m, 7H), 1.23 (m,1H).

Example 128 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-1′-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (Cpd. No. 128)

Synthesis of6-bromo-8-chloro-1′-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Light brown solid; Yield: 1.0 g,36%; MS (ESI) m/z 346.13 [M+1]⁺.

Synthesis of tert-butylN-[6-[(8-chloro-1′-methyl-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-6-yl)amino]pyrimidin-4-yl]carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 60 mg, 14%;¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H), 9.63 (s, 1H), 8.84 (s, 1H),8.80 (s, 1H), 8.44-8.42 (d, J=8.0 Hz, 1H), 7.47-7.45 (d, J=8.0 Hz, 1H),7.39-7.38 (m, 1H), 5.75 (s, 2H), 3.24-3.17 (m, 2H), 2.80-2.66 (m, 2H),2.39-2.35 (m, 2H), 2.32 (s, 3H), 1.50-1.47 (m, 2H), 1.23 (s, 9H).

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-8-chloro-1′-methyl-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (Cpd. No. 128)

The synthesis of compound 128 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 0.032 g,62%; MS (ESI) m/z 375.82 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.72 (brs,1H), 10.60 (s, 1H), 9.80 (s, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 7.81 (brs,2H), 6.53 (s, 1H), 3.66-3.33 (m, 6H), 2.78 (s, 3H), 1.91-1.88 (m, 2H).

Example 129 Synthesis of8-chloro-1′-methyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 129)

Synthesis of8-chloro-1′-methyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 129)

The synthesis of compound 129 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 65 mg, 31%;MS (ESI) m/z 360.80 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H),9.62 (s, 1H), 8.43-8.42 (d, J=5.6 Hz, 1H), 7.47-7.45 (d, J=4.8 Hz, 1H),3.25-3.17 (m, 2H), 2.80-2.78 (m, 2H), 2.39-2.33 (m, 2H), 2.24 (s, 3H),1.50-1.47 (m, 2H).

Example 130 Synthesis of1′,8-dimethyl-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 130)

Synthesis of6-bromo-1′,8-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 0.7 g, 25%; MS(ESI) m/z 326.19 [M+1]⁺.

Synthesis of1′,8-dimethyl-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 130)

The synthesis of compound 130 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 190 mg, 58%;MS (ESI) m/z 359.81 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (s, 1H),9.35 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.37-8.38 (d, J=5.88 Hz, 1H),7.35-7.36 (d, J=5.88 Hz, 1H), 3.01 (m, 2H), 2.95 (m, 1H), 2.50 (s, 2H),2.45 (s, 3H), 2.25 (s, 3H), 1.91-1.97 (m, 2H), 1.71-1.73 (m, 1H),1.48-1.51 (m, 1H).

Example 131 Synthesis of6′-(pyrimidin-4-ylamino)-1′-thioxo-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one(Cpd. No. 131)

Synthesis of6′-(pyrimidin-4-ylamino)-1′-thioxo-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one(Cpd. No. 131)

A vial containing tetrahydrofuran (10 mL) was charged with6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(1, 0.6 g, 1.93 mmol) and phosphorus pentasulfide (857 mg, 3.85 mmol).Seal the vial and heat the reaction mixture at 50° C. for 16 h. Aftercompletion, the reaction mass was diluted with 5% methanol indichloromethane (100 mL), washed with water (2×100 mL) and brinesolution (100 mL), dried over anhydrous sodium sulfate, concentratedunder vacuum. Crude material was purified by flash chromatography insilica gel in 3-4% methanol in dichloromethane, fraction were combinedconcentrated under reduced pressure. The product was triturated withmethanol, filtered washed with methanol (3 mL), ether (5 mL), driedunder high vacuum to obtain the desired product6′-(pyrimidin-4-ylamino)-1′-thioxo-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one(Cpd. No. 131) as light yellow solid. Yield: 0.050 g, 8%; MS (ESI) m/z328.41 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 9.46 (s, 1H),8.80-8.77 (d, 2H), 8.39-8.38 (d, 1H), 7.39-7.38 (d, 1H), 7.07-7.06 (d,1H), 2.97 (t, 2H), 1.78-1.72 (m, 5H), 1.59-1.56 (d, 1H), 1.26 (m, 1H).

Example 132 Synthesis of8′-chloro-1′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one(Cpd. No. 132)

Synthesis of8′-chloro-1′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one(Cpd. No. 132)

To a solution of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 1 g, 2.89 mmol) in chloroform (30 mL) was added triethylamine (1.21mL, 8.67 mmol) and O-methylhydroxylamine hydrochloride (241 mg, 2.89mmol). The reaction was stirred at reflux overnight. The resultingmixture was cooled to room temperature and washed with water. Theorganic layer was dried over magnesium sulfate, filtered andconcentrated. The crude was purified via flash column chromatography toafford8′-chloro-1′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-1′,2′-dihydro-5′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-5′-one(Cpd. No. 132).

Example 133 Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-5′-thioxo-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one(Cpd. No. 133)

Synthesis of ethyl3-chloro-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridine-2-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.42 g, 20%;MS (ESI) m/z 295 [M+1]⁺

Synthesis of ethyl3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxylate(4)

A vial was charged with3-chloro-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyridine-2-carboxylate(3, 0.35, 1.2 mmol) and pyridine (10 mL) was added. To the above mixturephosphorus pentasulfide (0.53 g, 2.4 mmol) was added and reaction washeated at 110° C. for 16 h. TLC showed presence of starting material andphosphorus pentasulfide (0.265 g, 1.2 mmol) was added again and heatedthe reaction to 115° C. for 24 h. The pyridine was removed under reducedpressure and water (20 mL) was added and extracted with 5% methanol indichloromethane (100 mL). The organic layer was washed with sodiumbicarbonate and brine and layer was concentrated to dryness to affordethyl3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxylate(4) as brownish yellow solid and used directly without furtherpurification. Yield: 350 mg, crude; MS (ESI) m/z 310.94 [M+1]⁺.

Synthesis of3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxamide(5)

Procedure K: A vial was charged with3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxylate(4, 0.35 g, 1.2 mmol) and methanolic ammonia (12 mL) was added. Themixture was slowly heated at 60-65° C. for 40 h when TLC showed completeconversion of starting material. The mixture was cooled and concentratedunder reduced pressure and triturated with diethyl ether (10 mL) toafford3-chloro-5-(pyrimidin-4-ylamino)-6-thioxo-1,6-dihydropyridine-2-carboxamide(5) as reddish brown solid. Yield: 350 mg, crude; MS (ESI) m/z 282.04[M+1]⁺.

Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-5′-thioxo-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one(Cpd. No. 133)

The synthesis of compound 133 was carried out as described above usingthe general protocol of Procedure A. Yellow solid; Yield: 17 mg, 4%; MS(ESI) m/z 362.06 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (brs, 1H),9.93 (s, 1H), 9.00 (s, 1H), 8.90 (s, 1H), 8.51 (d, J=5.6 Hz, 1H), 7.43(d, J=6.0 Hz, 1H), 4.22-3.12 (m, 2H), 1.84-1.78 (m, 2H), 1.75-1.60 (m,3H), 1.54-1.47 (m, 2H), 1.30-1.22 (m, 1H).

Example 134 Synthesis of8′-chloro-5′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one(Cpd. No. 134)

Synthesis of8′-chloro-5′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one(Cpd. No. 134)

To a solution of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 1 g, 2.89 mmol) in chloroform (30 mL) is added triethylamine (1.21mL, 8.67 mmol) and O-methylhydroxylamine hydrochloride (241 mg, 2.89mmol). The reaction is stirred at reflux overnight. The resultingmixture is cooled to room temperature and washed with water. The organiclayer is dried over magnesium sulfate, filtered and concentrated. Thecrude is purified via flash column chromatography to afford8′-chloro-5′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one(Cpd. No. 134).

Example 135 Synthesis of8′-chloro-2′-cyclopropyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 135)

Synthesis of6′-bromo-8′-chloro-2′-cyclopropyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

To a solution of6′-bromo-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 1 g, 3.02 mmol) in 1,2-dichloroethane (15 mL) is addedcyclopropylboronic acid (2, 0.58 g, 6.80 mmol), copper(II) acetate (0.59g, 3.23 mmol), 2,2′-bi-pyridyl (0.50 g, 3.23 mmol) and sodium carbonate(0.73 g, 6.86 mmol). The reaction is stirred at 70° C. overnight. Thereaction is cooled to room temperature. The resulting mixture isquenched with saturated aqueous ammonium chloride solution and extractedwith dichloromethane. The organic is dried over magnesium sulfate,filtered and concentrated. The crude is purified via columnchromatography to afford6′-bromo-8′-chloro-2′-cyclopropyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3).

Synthesis of8′-chloro-2′-cyclopropyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 135)

The synthesis of compound 135 is carried out as described above usingthe general protocol of Procedure H.

Example 136 Synthesis of8′-chloro-2′-(pyridin-3-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 136)

Synthesis of8′-chloro-2′-(pyridin-3-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 136)

To a solution of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 450 mg, 1.3 mmol) and 3-iodopyridine (800 mg, 3.9 mmol) indimethylformamide (10 mL) in a vial, cesium carbonate (550 mg, 1.6 mmol)was added and the mixture was degassed with argon for 15 min. To thismixture 1,10,-phenanthroline (37 mg, 0.2 mmol), copper(I) iodide (12 mg,0.05 mmol), XantPhos (26 mg, 0.065 mmol) were added and the reaction washeated the mixture at 130° C. for 26 h. TLC showed consumption ofstarting material, the reaction mixture was filtered over celite bed andwashed with 5% methanol in dichloromethane followed by concentration ofthe filtrate. Obtained solid was purified by Combi-Flash chromatographyon neutral alumina using 3% methanol/dichloromethane as a eluent,appropriate fractions were concentrated under reduced pressure to afford8′-chloro-2′-(pyridin-3-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 136) as yellow solid. Yield: 0.025 g, 4.6%; MS (ESI) m/z423.12 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 8.61 (d, J=2.0Hz, 1H), 8.58 (s, 1H), 8.49 (d, J=4.8 Hz, 1H), 8.33 (d, J=6.0 Hz, 1H),8.03 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.47 (dd, J=4.4, 8.8 Hz, 1H), 6.65(d, J=6.0 Hz, 1H), 2.85-2.79 (m, 2H), 1.74-1.53 (m, 6H), 1.17-1.14 (m,1H).

Example 137 Synthesis of7′-fluoro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 137)

Synthesis of methyl 4-fluoropicolinate (2)

To a solution of 4-fluoropicolinic acid (1, 1 g, 7.09 mmol) in toluene(20 mL) and methanol (5 mL) at room temperature is added(trimethylsilyl)diazomethane (2 M in hexanes, 5.32 mL, 10.64 mmol)dropwise. The reaction is stirred at 80° C. for 2 h. The resultingmixture is concentrated and purified via flash chromatography to affordmethyl 4-fluoropicolinate (2).

Synthesis of 4-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (3)

To a solution of methyl 4-fluoropicolinate (2, 1 g, 6.45 mmol) indichloromethane (30 mL) is added urea hydrogen peroxide (1.27 g, 13.54mmol) and trifluoroacetic anhydride (1.79 mL, 12.9 mmol). The reactionis stirred at room temperature for 2 h. The resulting mixture is pourinto 0.5 M hydrochloric acid and extracted with dichloromethane. Theorganic layer is washed with saturated aqueous sodium bicarbonatesolution, dried over magnesium sulfate, filtered and concentrated. Thecrude is purified via flash chromatography to afford methyl4-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (3).

Synthesis of methyl 4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (4)

To a solution of methyl 4-fluoro-2-(methoxycarbonyl)pyridine 1-oxide (3,1 g, 5.84 mmol) in dimethylformamide (25 mL) is added trifluoroaceticanhydride (1.62 mL, 11.68 mmol). The reaction is stirred at 50° C. for 3h. The resulting mixture is concentrated and purified via flashchromatography to afford methyl4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (4).

Synthesis of methyl5-bromo-4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (5)

To a solution of methyl 4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate(4, 1 g, 5.84 mmol) in acetonitrile (25 mL) is added N-bromosuccinimide(1.56 g, 8.76 mmol). The reaction is stirred at reflux for 2 h. Theresulting mixture is pour into half saturated aqueous sodium bisulfiteand extracted with ethyl acetate. The organic layers are combined, driedover magnesium sulfate, filtered and concentrated. The crude is purifiedvia flash chromatography to afford methyl5-bromo-4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxylate (5).

Synthesis of 5-bromo-4-fluoro-6-oxo-1,6-dihydropyridine-2-carboxamide(6)

The synthesis of intermediate 6 is carried out as described above usingthe general protocol of Procedure K.

Synthesis of6′-bromo-7′-fluoro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(8)

The synthesis of intermediate 8 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of7′-fluoro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 137)

The synthesis of compound 137 is carried out as described above usingthe general protocol of Procedure H.

Example 138 Synthesis of8-phenyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 138)

Synthesis of8-phenyl-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 138)

The synthesis of compound 138 was carried out as described above usingthe general protocol of Procedure G. Off white solid; Yield: 0.15 g,67%; MS (ESI) m/z 388.48 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s,1H), 9.49 (s, 1H), 8.74 (s, 1H), 8.71 (s, 1H), 8.38 (d, J=5.84 Hz, 1H),7.47-7.35 (m, 6H), 3.10-3.04 (m, 2H), 1.76-1.49 (m, 7H), 1.04-1.02 (m,1H).

Example 139 Synthesis of8′-(oxetan-2-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 139)

Synthesis of8′-chloro-2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2)

To a solution of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 1 g, 2.89 mmol) in dimethylformamide (15 mL) is added sodium hydride(0.21 g, 8.67 mmol) and 4-methoxybenzyl chloride (1.57 mL, 11.56 mmol).The reaction is stirred at room temperature overnight. The resultingmixture is poured into iced water and extracted with dichloromethane.The organic layer is dried over magnesium sulfate, filtered andconcentrated. The crude is purified via column chromatography to afford8′-chloro-2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2).

Synthesis of2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbonitrile(3)

To a solution of8′-chloro-2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2, 1 g, 1.71 mmol)) in acetonitrile (20 mL) is added potassium cyanide(0.17 g, 2.56 mmol), tributyltin chloride (0.038 mL, 0.14 mmol). Themixture is degassed and followed by the addition oftris(dibenzylideneacetone)dipalladium(0) (64 mg, 0.07 mmol) andtri-tert-butylphosphine (63 mg, 0.31 mmol). The mixture is degassed twomore times. The reaction is stirred at 80° C. overnight. The resultingmixture is cooled to room temperature and filtered through a pad ofcelite. The filtrate is concentrated and purified via columnchromatography to afford2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbonitrile(3).

Synthesis of2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbaldehyde (4)

To a solution of2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbonitrile(3, 1 g, 1.73 mmol) in dichloromethane (20 mL) at 0° C. is addeddiisobutylaluminum hydride (1 M in dichloromethane, 3.46 mL, 3.46 mmol)dropwise. The reaction is stirred at 0° C. for 2 h. The resultingmixture is poured into saturated aqueous Rochelle's salt solution. Thebiphasic mixture is stirred overnight and filtered. The filtrate isextracted with dichloromethane. The organic is dried over magnesiumsulfate, filtered and concentrated. The crude is purified via columnchromatography to afford2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbaldehyde(4).

Synthesis of2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxiran-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(5)

A suspension of sodium hydride (50% dispersion washed free of mineraloil, 90 mg, 1.87 mmol) in dimethylsulfoxide (2 mL) is heated to 65° C.under argon for 1 h. The oil bath is removed and to the clear solutionis added tetrahydrofuran (2 mL). The solution is cooled to −15° C. andtreated with a solution of trimethylsulfonium iodide (0.35 g, 1.72 mmol)in dimethylsulfoxide (2 mL). After 3 min a solution of2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbaldehyde(4, 1 g, 1.72 mmol) in 3 ml. of tetrahydrofuran is added. The reactionis stirred overnight. The resulting mixture is poured into water andextracted with ethyl acetate. The extracts are washed with water, driedand evaporated to afford2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxiran-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(5).

Synthesis of2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxetan-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(6)

Potassium tert-butoxide (0.23 g, 2.02 mmol) is added to a solution oftrimethylsulfoxonium iodide (0.44 g, 2.02 mmol) in tert-butanol (10 mL)at room temperature. After 15 min, a solution of2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxiran-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(5, 1 g, 1.68 mmol) in dimethylsulfoxide (5 mL) is added dropwise. Thereaction is stirred at 50° C. overnight. The resulting mixture isquenched with brine and extracted with ethyl acetate. The combinedextracts are dried over magnesium sulfate. After filtration andconcentration, the residue is purified by flash column to afford2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxetan-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(6).

Synthesis of8′-(oxetan-2-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 139)

2′-(4-Methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxetan-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(6, 100 mg, 0.16 mmol) is dissolved in trifluoroacetic acid (5 mL). Thereaction is stirred at room temperature overnight. The resulting mixtureis concentrated and purified via column chromatography to afford8′-(oxetan-2-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 139).

Example 140 Synthesis of8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-vinyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 140)

Synthesis of6-bromo-8-chloro-3-methyl-3-vinyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of8-chloro-3-methyl-6-(pyrimidin-4-ylamino)-3-vinyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 140)

The synthesis of compound 140 is carried out as described above usingthe general protocol of Procedure H.

Example 141 Synthesis of8-chloro-3-methyl-3-(prop-1-yn-1-yl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 141)

Synthesis of6-bromo-8-chloro-3-methyl-3-(prop-1-yn-1-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of8-chloro-3-methyl-3-(prop-1-yn-1-yl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 141)

The synthesis of compound 141 is carried out as described above usingthe general protocol of Procedure H.

Example 142 Synthesis of4-08′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidine-5-carbonitrile(Cpd. No. 142)

Synthesis of4-((8′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidine-5-carbonitrile(Cpd. No. 142)

The synthesis of compound 142 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.25 g, 76%;MS (ESI) m/z 371.38 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H),9.06 (s, 1H), 9.03 (s, 1H), 8.98 (s, 1H), 8.59 (s, 1H), 2.93-2.87 (m,2H), 1.93-1.88 (m, 2H), 1.75-1.54 (m, 5H), 1.27-1.23 (m, 1H).

Example 143 Synthesis of8′-chloro-6′-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 143)

Synthesis of 5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-amine (3)

To a solution of 5-iodopyrimidin-4-amine (1, 0.5 g, 2.26 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (2,0.56 g, 2.71 mmol) in dioxane/water (15 mL, 9:1.5) in a vial, was addedcesium carbonate (1.84 g, 5.66 mmol) and the mixture was degassed withargon for 15 min. To this mixture was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.09 g, 0.11 mmol) and then heated to 110° C. for16 h. TLC showed consumption of starting material, cooled the reactionmixture to ambient temperature, filtered the mass over celite bed,washed with dichloromethane (30 mL) followed by concentration offiltrate. The crude compound was purified by flash column chromatographyeluting with 3% methanol in dichloromethane. The desired fractions wereconcentrated to dryness to afforded as5-(1-methylpyrazol-4-yl)pyrimidin-4-amine (3) as off white solid; Yield:0.2 g, 50%; MS (ESI) m/z 176.08 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.28(s, 1H), 8.13 (s, 1H), 8.01 (s, 1H), 7.70 (s, 1H), 6.61 (s, 2H), 3.87(s, 3H).

Synthesis of8′-chloro-6′-((5-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 143)

The synthesis of compound 143 was carried out as described above usingthe general protocol of Procedure H. Pale yellow solid; Yield: 0.14 g,36%; MS (ESI) m/z 426.44 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s,1H), 8.83 (s, 1H), 8.76-8.73 (s, 2H), 8.46 (s, 1H), 8.17 (s, 1H), 7.85(s, 1H), 3.96 (s, 3H), 2.86 (m, 2H), 1.74-1.49 (m, 7H), 1.25 (m, 1H).

Example 144 Synthesis of8′-chloro-6′-((5-ethynylpyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 144)

Synthesis of 5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (3)

5-Iodopyrimidin-4-amine (1, 1 g, 4.52 mmol), copper(I) iodide (172 mg,0.90 mmol), ethynyl(trimethyl) silane (2, 0.67 g, 6.79 mmol),triphenylphosphine (119 mg, 0.45 mmol), triethylamine (0.914 mg, 9.04mmol) and palladium(II) chloride (80 mg, 0.45 mmol) were taken in aflask and tetrahydrofuran was added followed by degassing with argon for5 minutes. The reaction mixture was stirred at 40° C. for 16 h. Aftercompletion, reaction mixture was filtered over celite bed and resultingfiltrate was concentrated to afford5-(2-trimethylsilylethynyl)pyrimidin-4-amine (3) as a brown solid.Yield: 0.76 g, 88%; MS (ESI) m/z 192.1 [M+1]⁺.

Synthesis of8′-chloro-6′-((5-((trimethylsilyl)ethynyl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure B. Yellow solid. Yield: 0.30 g, 45%;MS (ESI) m/z 441.99 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H),9.06 (s, 1H), 8.88 (s, 1H), 8.67 (m, 2H), 5.80 (m, 1H), 2.94-2.89 (m,2H), 1.74-1.57 (m, 7H), 1.23 (m, 1H), 0.34 (s, 9H).

Synthesis of8′-chloro-6′-((5-ethynylpyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 144)

A flask was charged with8′-chloro-6′-((5-((trimethylsilyl)ethynyl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(5, 300 mg, 0.67 mmol) and methanol (20 mL) followed by addition ofpotassium carbonate (469 mg, 3.39 mmol) at room temperature and reactionmixture was stirred for 16 h. After completion, solvent was concentratedunder reduced pressure and the resulting residue was further washed withwater followed by diethyl ether and pentane to afford8′-chloro-6′-((5-ethynylpyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 144) as yellow solid. Yield: 100 mg, 40%; MS (ESI) m/z 370.09[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H), 8.99 (s, 1H), 8.90(s, 1H), 8.70 (s, 2H), 5.22 (s, 1H), 2.90 (brs, 2H), 1.73-1.64 (m, 2H),1.61-1.56 (m, 3H), 1.56-1.53 (m, 2H), 1.27 (m, 1H).

Example 145 Synthesis of6′-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 145)

Synthesis of6′-((1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 145)

To a suspension of6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(1, 0.5 g, 1.51 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (2, 0.2 g,1.51 mmol) in tert-butanol (20 mL) in a vial, potassium phosphate (0.96g, 4.54 mmol) was added and the reaction mixture was degassed with argonfor 15 min. To this mixture XantPhos (4 mg, 0.08 mmol) and Pd₂(dba)₃ (7mg, 0.08 mmol) was added and the reaction mixture was further degassedwith argon for 5 min. The reaction mixture was heated at 90° C. for 18h. TLC showed consumption of starting material, the reaction mixture wasfiltered over celite bed and washed with dichloromethane followed byconcentration of the filtrate. The crude was stirred with methanol (10mL) and filtered. The resulting solid was further washed with diethylether (20 mL) and dried under vacuum to afford8-chloro-6-(1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 145). Yield: 0.037 g, 6%; MS (ESI) m/z 386.36 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 10.39 (s, 1H), 9.55 (s, 1H), 8.91 (s, 1H), 8.61 (s,2H), 2.97 (m, 2H), 1.76-1.56 (m, 7H), 1.23 (m, 1H).

Example 146 Synthesis of8-chloro-6-(3H-triazolo[4,5-d]pyrimidin-7-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 146)

Synthesis of 2-methyl-N-(3H-triazolo[4,5-d]pyrimidin-7-yl)propanamide(3)

To a vial 3H-triazolo[4,5-d]pyrimidin-7-amine (1, 2.0 g, 14.69 mmol) wasadded in dimethylformamide (20 mL) followed by addition of2-methylpropanoyl 2-methylpropanoate (2, 6.97 g, 44.08 mmol). Thereaction mixture was stirred at 160° C. for 1 h. After completion, thereaction was cooled to room temperature and diluted with water (100 mL).The precipitated white solid was filtered and dried under vacuum tooffer 2-methyl-N-(3H-triazolo[4,5-d]pyrimidin-7-yl)propanamide (3) aswhite solid. Yield: 2.5 g, 82%; MS (ESI) m/z 205.2 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 15.75 (m, 2H), 11.57 (s, 1H), 8.80 (s, 1H), 2.94-2.97(m, 1H), 1.20 (d, J=6.8 Hz, 6H).

Synthesis ofN-((2-(trimethylsilyl)ethoxy)methyl)-N-(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)isobutyramide(4)

To a stirred solution of2-methyl-N-(3H-triazolo[4,5-d]pyrimidin-7-yl)propanamide (3, 1.5 g, 7.27mmol) in dimethylformamide (20 mL), sodium hydride (0.26 g, 10.91 mmol)was added portion wise in 10 min at 0° C. The above suspension wasstirred for 10 min at 0° C. and 2-(trimethylsilyl)ethoxymethyl chloride(1.82 g, 10.91 mmol) was added at the same temperature under nitrogen.The reaction was stirred at room temperature for 6 h. After completion,the reaction mass was quenched with saturated aqueous solution ofammonium chloride and crude was extracted with dichloromethane (2×50mL). The organics were then separated, dried (magnesium sulfate) andconcentrated to dryness under vacuum and the crude was purified by flashchromatography eluting with 5% ethyl acetate in hexane. Concentration ofthe desired fractions provides2-methyl-N-(2-trimethylsilylethoxy)-N-[3-(2-trimethylsilylethoxy)triazolo[4,5-d]pyrimidin-7-yl]propanamide(4) as transparent viscous oil. Yield: 1.1 g, 44%; MS (ESI) m/z 467.42[M+1]⁺.

Synthesis ofN,3-bis((2-(trimethylsilyl)ethoxy)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure I. Yellow solid; Yield: 0.8 g, 94%; MS(ESI) m/z 397 [M+1]⁺.

Synthesis of8′-chloro-6′-(((2-(trimethylsilyl)ethoxy)methyl)(3-((2-(trimethylsilyl)ethoxy)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1,5′-dione(7)

The synthesis of intermediate 7 was carried out as described above usingthe general protocol of Procedure H. Brown solid; Yield: 0.3 g, crude.

Synthesis of8-chloro-6-(3H-triazolo[4,5-d]pyrimidin-7-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 146)

To a stirred solution of8-chloro-6-[2-trimethylsilylethoxymethyl-[3-(2-trimethylsilylethoxymethyl)triazolo[4,5-d]pyrimidin-7-yl]amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(7, 0.3 g, 0.46 mmol) in dichloromethane (15 mL), trifluoroacetic acid(5 mL, 4.63 mmol) was added drop wise at 0° C. The reaction mass wasstirred for overnight at room temperature. After completion, reactionmass was concentrated and co-evaporated with diethyl ether. The crudewas then dissolved in tetrahydrofuran/ethanol solution and potassiumhydroxide (5 mL, 0.46 mmol) solution (3 M in water) was added andstirred the mixture for 16 h. After completion of the reaction theaqueous layer was separated and organic layer was dried over sodiumsulfate, filtered and concentrated to get crude. The crude was washedwith methanol and n-pentane and dried to afford8-chloro-6-(3H-triazolo[4,5-d]pyrimidin-7-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 146) as brown solid. Yield: 70 mg, 39%; MS (ESI) m/z 387.39[M+1]⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ 10.45 (brs, 1H), 9.29 (s, 1H), 8.88(s, 1H), 7.77 (s, 1H), 2.94 (t, J=2.32, 2H), 1.79-1.76 (m, 2H),1.67-1.51 (m, 5H), 1.27-1.23 (m, 1H).

Example 147 Synthesis of8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(Cpd. No. 147)

Synthesis ofN-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide(3)

To a stirred solution ofN-benzyl-3-((tert-butyldimethylsilyl)oxy)propan-1-amine (2, 3.0 g, 12.9mmol) in dimethylformamide (50 mL),5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (1, 3.6 g,12.9 mmol), HBTU (6.4 g, 16.9 mmol) and N,N-diisopropylethylamine (2.2g, 16.9 mmol) were added in a vial at room temperature and stirred themixture for 16 h. TLC showed completion of reaction, the reactionmixture was quenched with aqueous sodium bicarbonate solution andextracted with ethyl acetate (250 mL). The organic layer was dried oversodium sulfate and solvent was removed under reduced pressure to affordN-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (3) as yellow liquid. Yield: 3.0 g, 47%;MS (ESI) m/z 495.24 [M−1]⁻.

Synthesis ofN-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide(4)

To a stirred solution ofN-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (3, 3.0 g, 6.0mmol) in dioxane (20 mL), hydrogenchloride in dioxane (20 mL) was addedat room temperature and the mixture was stirred for 16 h. Aftercompletion, the solvent was removed and the reaction was basified withaqueous sodium bicarbonate solution and extracted with 5%methanol/dichloromethane (3×200 mL). The organic layer was dried oversodium sulfate and solvent was removed under reduced pressure to getN-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4) as brown liquid. Yield: 2.2 g, 95%;MS (ESI) m/z 381.22 [M−1]⁻.

Synthesis of 2-benzyl-8-bromo-10-methyl-2, 3, 4, 5-tetrahydropyrido [1,2-a][1,4]diazepine-1, 7-dione (5)

To a stirred solution ofN-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide(4, 1.5 g, 3.9 mmol) in tetrahydrofuran (30 mL), triphenylphosphine (1.5g, 5.9 mmol) and diisopropyl azodicarboxylate (1.2 g, 5.9 mmol) wereadded at 0° C. The reaction was stirred at room temperature for 16 h.After completion, solvent was removed under reduced pressure and crudewas purified by flash chromatography eluting with 40% ethyl acetate inhexane. Appropriate fractions were concentrated under reduced pressureto afford2-benzyl-8-bromo-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(5) as yellow solid. Yield: 0.9 g, 64%; MS (ESI) m/z 361.18 [M+1]⁺.

Synthesis of8-((6-(di-(tert-butoxycarbonyl)-amino)pyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(7)

The synthesis of intermediate 7 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.9 g, 69%; MS(ESI) m/z 591.66 [M+1]⁺.

Synthesis of8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(8)

The synthesis of intermediate 8 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.59 g, 99%;MS (ESI) m/z 391.32 [M+1]⁺.

Synthesis of8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(Cpd. No. 147)

A vial was charged with8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(8, 0.3 g, 76.9 mmol) and trifluoroacetic acid (7.0 mL) was added andthe reaction mixture was heated under microwave at 150° C. for 20 min.TLC showed completion of the reaction and the mixture was cooled toambient temperature and this was then basified with aqueous sodiumbicarbonate solution and extracted with 5% methanol/dichloromethane(3×200 mL). The organic layer was dried over sodium sulfate and solventwas removed under reduced pressure to afford8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(Cpd. No. 147) as a brown solid. Yield: 0.06 g, 26%; MS (ESI) m/z 301.15[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.44 (m, 2H), 8.15 (s,1H), 6.52 (m, 2H), 6.13 (s 1H), 5.05 (m, 1H), 3.17 (m, 2H), 2.95 (m,1H), 2.13 (s, 3H), 1.87 (m, 2H).

Example 148 Synthesis of3,3-di-tert-butyl-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 148)

Synthesis of6-bromo-3,3-di-tert-butyl-8-chloro-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of3,3-di-tert-butyl-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 148)

The synthesis of compound 148 is carried out as described above usingthe general protocol of Procedure H.

Example 149 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-3,3-di(thiophen-2-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 149)

Synthesis of6-bromo-8-chloro-3,3-di(thiophen-2-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-3,3-di(thiophen-2-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 149)

The synthesis of compound 149 is carried out as described above usingthe general protocol of Procedure H.

Example 150 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-3,3-di(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 150)

Synthesis of6-bromo-8-chloro-3,3-di(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-3,3-di(thiophen-3-yl)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 150)

The synthesis of compound 150 is carried out as described above usingthe general protocol of Procedure H.

Example 151 Synthesis of8-chloro-3,3-dipropyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 151)

Synthesis of 6-bromo-8-chloro-3, 3-dipropyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 0.23 g,66%; MS (ESI) m/z 347.01 [M+1]⁺.

Synthesis of8-chloro-3,3-dipropyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 151)

The synthesis of compound 151 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.14 g,57%; MS (ESI) m/z 362.13 [M+1]⁺; ¹H-NMR (400 MHz, DMSO-d₆) δ 9.64 (s,1H), 9.59 (s, 1H), 8.85 (s, 1H), 8.81 (s, 1H), 8.44 (d, J=5.88 Hz, 1H),7.42 (d, J=5.88, 1H), 2.54 (m, 2H), 1.86 (t, J=10.9 Hz, 2H), 1.15 (m,2H), 0.82 (m, 8H).

Example 152 Synthesis of3,3-bis(2-aminoethyl)-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 152)

Synthesis of2,2′-((6-bromo-8-chloro-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-3,3-diyl)bis(ethane-2,1-diyl))bis(isoindoline-1,3-dione)(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of2,2′-((8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-3,3-diyl)bis(ethane-2,1-di yl))bis(isoindoline-1,3-dione) (5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of3,3-bis(2-aminoethyl)-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 152)

The synthesis of compound 152 is carried out as described above usingthe general protocol of Procedure C.

Example 153 Synthesis of8-chloro-3,3-bis(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 153)

Synthesis of dimethyl2,2′-(6-bromo-8-chloro-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-3,3-diyl)diacetate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 0.65 g,27%; MS (ESI) m/z 407.18 [M−1]⁻.

Synthesis of dimethyl2,2′-(8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-3,3-diyl)diacetate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.34 g,51%; MS (ESI) m/z 422.49 [M+1]⁺.

Synthesis of 8-chloro-3,3-bis(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione (Cpd. No. 153)

To a slurry of lithium aluminum hydride (71 mg, 1.9 mmol) intetrahydrofuran (3 mL) at 0° C. a solution of dimethyl2,2′-(8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-3,3-diyl)diacetate(5, 280 mg, 0.66 mmol) in tetrahydrofuran (2 mL) was added slowly. Afterconsumption of starting material the reaction mixture was quenched with10% sodium hydroxide solution (1 mL), diluted with 10 ml of ethylacetate. The organic layer was separated and dried over anhydrous sodiumsulfate and concentrated under reduce pressure to afford the residue.The residue was purified prep HPLC to afford8-chloro-3,3-bis(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 153) as yellow solid. Yield: 0.047 g, 19%; MS (ESI) m/z 366.09[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.58-9.57 (brs, 1H), 8.83 (s, 1H),8.75 (s, 1H), 8.42 (d, J=5.6 Hz, 1H), 7.44-7.42 (d, J=5.6 Hz, 1H), 4.44(brs, 2H), 3.34-3.26 (m, 4H), 2.79-3.73 (m, 2H), 2.11-2.08 (m, 2H).

Example 154 Synthesis of3,3-bis(aminomethyl)-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 154)

Synthesis of2,2′-((6-bromo-8-chloro-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-3,3-diyl)bis(methylene))bis(isoindoline-1,3-dione)(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of2,2′-((8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,2,3,5-tetrahydroimidazo[1,5-a]pyridine-3,3-diyl)bis(methylene))bis(isoindoline-1,3-dione) (5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of3,3-bis(aminomethyl)-8-chloro-6-(pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 154)

The synthesis of compound 154 is carried out as described above usingthe general protocol of Procedure C.

Example 155 Synthesis of8-chloro-1′-(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 155)

Synthesis of6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 3.5 g, 95%;MS (ESI) m/z 332.1 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.89 (s, 1H),9.45 (brs, 1H), 8.67 (brs, 1H), 8.30 (s, 1H), 3.70-3.36 (m, 4H),2.59-2.57 (m, 2H), 1.89-1.85 (m, 2H).

Synthesis of6-bromo-1′-[2-[tert-butyl(dimethyl)sily]oxyethyl]-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(4)

A flask was charged with6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (2, 0.5 g, 1.35 mmol) and acetonitrile (15 mL) was added.The reaction mass was cooled to 0° C. and potassium carbonate (281 mg,2.03 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (3, 388 mg,1.62 mmol) were added and reaction mass was heated at 80° C. for 2 days.After completion, the solvent was removed to get the crude compound. Thecrude compound was purified by flash column with 0.2% methanol indichloromethane. The desired fractions were concentrated to give6-bromo-1′-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(4) as a brown solid. Yield: 0.3 g, 45%; MS (ESI) m/z 373.01 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.62 (s, 1H), 8.25 (s, 1H), 3.69-3.63 (m, 4H),3.10-2.83 (m, 4H), 1.52 (m, 2H), 1.04 (s, 9H), 0.058 (s, 6H).

Synthesis of1′-[2-[tert-butyl(dimethyl)sily]oxyethyl]-8-chloro-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.15 g, 49%;MS (ESI) m/z 505 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H),9.63-9.60 (m, 1H), 8.84-8.75 (m, 2H), 8.43-8.36 (d, J=5.8 Hz, 1H), 7.47(d, J=5.8 Hz, 1H), 3.72-3.70 (m, 2H), 3.26-3.22 (m, 4H), 2.98-2.90 (m,4H), 1.53-1.46 (m, 2H), 1.33-1.29 (m, 2H), 0.95 (s, 9H), 0.058 (s, 6H).

Synthesis of8-chloro-1′-(2-hydroxyethyl)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 155)

The synthesis of compound 155 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.035 g, 49%;MS (ESI) m/z 391.34 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H),9.59 (m, 1H), 8.84 (d, J=16.48 Hz, 2H), 8.43-8.36 (d, J=5.8 Hz, 1H),7.47 (d, J=5.8 Hz, 1H), 4.43 (brs, 2H), 3.53 (brs, 2H), 3.21-3.16 (m,2H), 2.98-2.90 (m, 2H), 2.46-2.41 (m, 2H), 1.48-1.46 (m, 2H).

Example 156 Synthesis of8-chloro-1′-(2,2-difluoroethyl)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 156)

Synthesis of6-bromo-8-chloro-1′-(2,2-difluoroethyl)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3)

A flask was charged with6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (1, 0.5 g, 1.35 mmol) and acetonitrile (15 mL) was added.The reaction was cooled to 0° C. and N,N-diisopropylethylamine (1.17 mL,6.77 mmol) was added drop wise followed by addition of2-bromo-1,1-difluoro-ethane (2, 589 mg, 4.06 mmol). The reaction wasstirred at 60-110° C. for 48 h. After completion, the solvent wasremoved under reduced pressure to get the crude. The crude was purifiedby flash column using 1-3% methanol in dichloromethane. The desiredfractions were concentrated to get6-bromo-8-chloro-1′-(2,2-difluoroethyl)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3) as brown solid. Yield: 0.27 g, 50%; MS (ESI) m/z 396.11 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H), 8.25 (s, 1H), 6.29 (t, J=55.68Hz, 1H), 3.12-3.06 (m, 2H), 2.84-2.79 (m, 2H), 2.66-2.60 (m, 2H)1.49-1.46 (m, 2H).

Synthesis of8-chloro-1′-(2,2-difluoroethyl)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 156)

The synthesis of compound 156 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.13 g, 50%;MS (ESI) m/z 411.38 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.39 (s, 1H),9.60 (s, 1H), 8.84 (s, 1H), 8.80 (s, 1H), 8.43-8.36 (d, J=6.28 Hz, 1H),7.47 (d, J=5.8 Hz, 1H), 6.32 (t, J=56.0 Hz, 1H), 3.26-3.22 (m, 2H),2.98-2.90 (m, 2H), 2.88-2.79 (m, 2H), 2.70-2.64 (m, 2H), 1.51-1.48 (m,2H).

Example 157 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 157)

Synthesis of6-bromo-8-chloro-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off White solid; Yield: 1.1 g, 50%;MS (ESI) m/z 414.28 [M−1]⁻.

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 157)

The synthesis of compound 157 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.21 g, 41%;MS (ESI) m/z 429.24 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H),9.61 (s, 1H), 8.84-8.80 (m, 2H), 8.44-8.43 (m, 1H), 7.46-7.44 (m, 1H),3.28-3.17 (m, 4H), 2.97-2.95 (m, 2H), 2.86-2.79 (m, 2H), 1.51-1.48 (d,2H).

Example 158 Synthesis of8′-chloro-8-methyl-6′-(pyrimidin-4-ylamino)-2′H-8-azaspiro[bicyclo[3.2.1]octane-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 158)

Synthesis of6′-bromo-8′-chloro-8-methyl-2′H-8-azaspiro[bicyclo[3.2.1]octane-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Brown solid; Yield: 0.15 g, 10%; MS(ESI) m/z 372.21 [M+1]⁺.

Synthesis of8′-chloro-8-methyl-6′-(pyrimidin-4-ylamino)-2′H-8-azaspiro[bicyclo[3.2.1]octane-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 158)

The synthesis of compound 158 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.029 g, 20%;MS (ESI) m/z 387.35 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H),9.53 (s, 1H), 8.84 (s, 1H), 8.80 (s, 1H), 8.43 (d, J=5.88 Hz, 1H), 7.46(d, J=5.84 Hz, 1H), 3.23 (m, 4H), 2.59 (s, 3H), 1.94 (s, 4H). 1.40 (d,J=12.8 Hz, 2H).

Example 159 Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-8-azaspiro[bicyclo[3.2.1]octane-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 159)

Synthesis of tert-butyl6′-bromo-8′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-8-azaspiro[bicyclo[3.2.1]octane-3,3′-imidazo[1,5-a]pyridine]-8-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure E.

Synthesis of tert-butyl8′-chloro-1′,5′-dioxo-6′-(pyrimidin-4-ylamino)-1′,5′-dihydro-2′H-8-azaspiro[bicyclo[3.2.1]octane-3,3′-imidazo[1,5-a]pyridine]-8-carboxylate(5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-8-azaspiro[bicyclo[3.2.1]octane-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 159)

The synthesis of compound 159 is carried out as described above usingthe general protocol of Procedure F.

Example 160 Synthesis of2-(8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 160)

Synthesis of2-(6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(3)

A flask was charges with6-bromo-8-chloro-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (1, 0.5 g, 1.35 mmol) and acetonitrile (15 mL) was added.The reaction mass was cooled to 0° C. and potassium carbonate (281 mg,2.03 mmol) was added followed by addition of 2-bromoacetonitrile (2, 218mg, 1.63 mmol). The reaction mass was stirred at room temperature for 10h. After completion, the solvent was removed under reduced pressure toget the crude. The crude was purified by Biotage snap using 1-3%methanol in dichloromethane. The desired fractions were concentrated toget3-(6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-yl)propanenitrile(3) as brown solid. Yield: 0.42 g, 83%; MS (ESI) m/z 373.18 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.25 (s, 1H), 3.75 (s, 2H),3.15-3.10 (m, 2H), 2.87-2.72 (m, 2H), 2.66-2.60 (m, 2H) 1.57-1.54 (m,2H).

Synthesis of2-[8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-yl]acetonitrile(Cpd. No. 160)

The synthesis of compound 160 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.2 g, 49%; MS(ESI) m/z 385.97 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 9.62(s, 1H), 8.84 (s, 1H), 8.80 (s, 1H), 8.43-8.36 (d, J=6.28 Hz, 1H), 7.47(d, J=5.8 Hz, 1H), 3.75 (s, 2H), 3.26-3.22 (m, 2H), 2.98-2.90 (m, 2H),2.67-2.61 (m, 2H), 1.60-1.57 (m, 2H).

Example 161 Synthesis of8-chloro-1′-(pyrimidin-4-yl)-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 161)

Synthesis of6-bromo-8-chloro-1′-(pyrimidin-4-yl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yellow solid. Yield: 0.1 g, 61%; MS(ESI) m/z 410.02 [M+1]⁺.

Synthesis of8-chloro-1′-(pyrimidin-4-yl)-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 161)

The synthesis of compound 161 was carried out as described above usingthe general protocol of Procedure B. Yellow solid. Yield: 0.06 g, 23%;MS (ESI) m/z 425.34 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H),9.59 (s, 1H), 8.83 (s, 1H), 8.79 (s, 1H), 8.56 (s, 1H), 8.41 (d, J=5.84Hz, 1H), 8.25 (d, J=6.08 Hz, 1H), 7.39 (d, J=5.72 Hz, 1H), 7.00 (d,J=6.01 Hz, 1H), 4.53 (brs, 2H), 3.28 (m, 2H), 3.05 (m, 2H), 1.68 (d,J=12.6 Hz, 1H).

Example 162 Synthesis of8-chloro-4′-(methylamino)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 162)

Synthesis of6′-bromo-4′-chloro-4-(methylamino)spiro[cyclohexane-1,1′-isoindole]-3′,7′(2′H,7a′H)-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 0.72 g, crude; MS (ESI) m/z359.65 [M−1]⁻.

Synthesis of tert-butylN-(6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,4′-cyclohexane]-1′-yl)-N-methyl-carbamate(4)

To a mixture of6-bromo-8-chloro-4′-(methylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(3, 0.72 g, 1.99 mmol) in 1,4-dioxane (10 mL) and water (10 mL),potassium hydroxide (0.56 g, 9.94 mmol) was added followed by additionof tert-butoxycarbonyl tert-butyl carbonate (651 mg, 2.98 mmol) andstirred the mixture at room temperature for 24 h. On completion ofreaction, the resulting mixture was filtered. The precipitate wasdissolved it in 10% methanol in dichloromethane. Organic layer waswashed with water and brine, dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to get tert-butylN-(6-bromo-8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-c]pyridine-3,4′-cyclohexane]-1′-yl)-N-methyl-carbamate(4) as white solid. Yield: 0.9 g, 98%; ¹H NMR (400 MHz, DMSO-d₆) δ 10.76(s, 1H), 8.26 (s, 1H), 4.00-3.97 (m, 1H), 2.98 (brs, 2H), 2.73 (s, 3H),1.98-1.81 (m, 2H), 1.73-1.60 (m, 4H), 1.41 (s, 9H).

Synthesis of tert-butylN-[8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,4′-cyclohexane]-1′-yl]-N-methyl-carbamate(6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.11 g,21%; MS (ESI) m/z 475.31 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s,1H), 9.67 (s, 1H), 8.84 (s, 1H), 8.80 (s, 1H), 8.44 (d, J=5.6, 1H), 7.46(s, 1H), 3.94-3.87 (m, 1H), 3.12-3.06 (m, 2H) 2.75 (s, 3H), 1.89-1.85(m, 3H), 1.66-1.64 (m, 4H), 1.41 (s, 3H).

Synthesis of8-chloro-4′-(methylamino)-6-(pyrimidin-4-ylamino)spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dionehydrochloride (Cpd. No. 162)

The synthesis of compound 162 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.060 g, 69%;MS (ESI) m/z 375.26 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.07 (s, 1H),8.60 (s, 1H), 8.46 (d, J=6.8 Hz, 1H), 7.58 (d, J=6.0 Hz, 1H), 3.16-3.13(m, 1H), 3.04-2.98 (m, 2H), 2.57 (s, 3H), 2.13-2.10 (m, 2H), 1.72-1.66(m, 4H).

Example 163 Synthesis of1′-acetyl-8-chloro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione (Cpd. No. 163)

Synthesis of1′-acetyl-6-bromo-8-chloro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 0.60 g,81%; MS (ESI) m/z 375.41 [M+1]⁺.

Synthesis1′-acetyl-8-chloro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 163)

The synthesis of compound 163 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.35 g, 43%;MS (ESI) m/z 389 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 9.66(s, 1H), 8.84 (s, 1H), 8.79 (s, 1H), 8.43 (d, J=5.84 Hz, 1H), 7.43 (d,J=5.92 Hz, 1H), 4.50 (d, J=12.64 Hz, 1H), 3.96 (d, J=2.95 Hz, 1H),3.10-3.07 (m, 1H), 3.06-3.03 (m, 1H), 2.06 (s, 3H), 1.68-1.59 (m, 2H).

Example 164 Synthesis of8′-chloro-1′,5′-dioxo-6′-(pyrimidin-4-ylamino)-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-4-carbonitrile(Cpd. No. 164)

Synthesis of6′-bromo-8′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-4-carbonitrile(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 0.75 g,53%; MS (ESI) m/z 354.08 [M−1]⁻.

Synthesis of8′-chloro-1′,5′-dioxo-6′-(pyrimidin-4-ylamino)-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-4-carbonitrile(Cpd. No. 164)

The synthesis of compound 164 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.21 g, 29%;MS (ESI) m/z 371.18 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H),9.58 (s, 1H), 8.84-8.78 (m, 2H), 8.44-8.39 (m, 1H), 7.44-7.43 (m, 1H),3.00-2.94 (m, 2H), 2.82-2.76 (m, 1H), 2.15-2.12 (m, 2H), 1.99-1.90 (m,3H), 1.67-1.64 (m, 2H).

Example 165 Synthesis of8-chloro-3,3-dimethyl-6-(pyrido[3,4-d]pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 165)

Synthesis of8-chloro-3,3-dimethyl-6-(pyrido[3,4-d]pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 165)

The synthesis of compound 165 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 25 mg, 8%; MS(ESI) m/z 357.34 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (brs, 1H),10.37 (s, 1H), 9.17 (s, 1H), 8.61 (m, 2H), 8.18 (d, J=5.24 Hz, 1H), 1.82(s, 6H).

Example 166 Synthesis of8-chloro-3,3-dimethyl-6-(pyrimido[5,4-c]pyridazin-8-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 166)

Synthesis of8-chloro-3,3-dimethyl-6-(pyrimido[5,4-c]pyridazin-8-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 166)

The synthesis of compound 166 is carried out as described above usingthe general protocol of Procedure H.

Example 167 Synthesis of8-chloro-3,3-dimethyl-6-(pyrimido[5,4-d]pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 167)

Synthesis of8-chloro-3,3-dimethyl-6-(pyrimido[5,4-d]pyrimidin-4-ylamino)-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 167)

The synthesis of compound 167 is carried out as described above usingthe general protocol of Procedure H.

Example 168 Synthesis of(Z)-8-chloro-6-((6-(2-cyclopropyl-3,3,3-trifluoroprop-1-en-1-yl)pyrimidin-4-yl)amino)-3-(3-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 168)

Synthesis of(Z)-8-chloro-6-((6-(2-cyclopropyl-3,3,3-trifluoroprop-1-en-1-yl)pyrimidin-4-yl)amino)-3-(3-fluorophenyl)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 168)

The synthesis of compound 168 is carried out as described above usingthe general protocol of Procedure H.

Example 169 Synthesis of6′-((6-amino-5-fluoropyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 169)

Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-chloro-5-fluoropyrimidin-4-yl)carbamate (2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure J. Off white solid; Yield: 2.3 g, 97%;MS (ESI) m/z 348 [M+1]⁺.

Synthesis of tert-butylN-tert-butoxycarbonyl-N-[6-(cyclopropanecarbonylamino)-5-fluoro-pyrimidin-4-yl]carbamate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.9 g, 38%;MS (ESI) m/z 397.29 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.6 (s, 1H),7.83 (s, 1H), 2.41 (brs, 1H), 1.46 (s, 18H), 1.30 (m, 4H).

Synthesis of N-(6-amino-5-fluoro-pyrimidin-4-yl)cyclopropanecarboxamide(5)

To a stirred solution of tert-butylN-tert-butoxycarbonyl-N-[6-(cyclopropanecarbonylamino)-5-fluoro-pyrimidin-4-yl]carbamate(4, 0.89 g, 2.25 mmol) in dichloromethane (20 mL), trifluoroacetic acid(20 mL, 2.25 mmol) was added at 0° C. and stirred the reaction mass atroom temperature for 16 h. After completion the reaction,trifluoroacetic acid was distilled and the crude compound was basifiedwith liquid ammonia. The solid precipitated out was filtered and driedto afford N-(6-amino-5-fluoro-pyrimidin-4-yl)cyclopropanecarboxamide (5)as off white solid. Yield: 0.4 g, 90%; MS (ESI) m/z 197.06 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 7.99 (s, 1H), 7.16 (s, 2H), 7.04(s, 1H), 2.06 (m, 1H), 0.82-0.78 (m, 4H).

Synthesis ofN-[6[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]-5-fluoro-pyrimidin-4-yl]cyclopropanecarboxamide(7)

The synthesis of intermediate 7 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.22 g, 40%;MS (ESI) m/z 447 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.87 (s, 1H),10.45 (s, 1H), 8.59-8.53 (m, 1H), 8.50-8.42 (m, 2H), 2.90 (m, 2H),1.98-1.98 (m, 1H), 1.77-1.53 (m, 8H), 0.82-0.84 (m, 4H).

Synthesis of6′-((6-amino-5-fluoropyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 169)

The synthesis of compound 169 was carried out as described above usingthe general protocol of Procedure I. Off white solid; Yield: 110 mg,65%; MS (ESI) m/z 378.9 [M+1]⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ 10.34 (brs,1H), 8.51 (s, 1H), 8.16 (s, 1H), 8.08 (s, 1H), 7.10 (s, 1H), 2.94 (t,J=2.32, 2H), 1.79-1.76 (m, 2H), 1.67-1.51 (m, 5H), 1.27-1.23 (m, 1H).

Example 170 Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-1′,8-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 170)

Synthesis of6-bromo-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. White solid; Yield: 0.7 g, 25%; MS(ESI) m/z 326.19 [M+1]⁺.

Synthesis of tert-butyl(6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidin]-6-yl)amino)pyrimidin-4-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.25 g, 64%;¹H NMR (400 MHz, DMSO-d₆) δ 10.92 (s, 1H), 9.80 (s, 1H), 9.10 (s, 1H),8.52-8.46 (m, 2H), 7.84 (m, 1H), 3.00-2.98 (m, 2H), 2.81-2.79 (m, 1H),2.43 (s, 3H), 2.21 (s, 3H), 2.03-1.90 (m, 3H), 1.70 (m, 1H), 1.48-1.4(s, 9H).

Synthesis of6-[(6-aminopyrimidin-4-yl)amino]-1′,8-dimethyl-spiro[2H-imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 170)

The synthesis of compound 170 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.1 g, 34%; MS(ESI) m/z 356.47 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 8.59(s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 6.52 (s, 2H), 6.14 (s, 1H),3.32-3.30 (m, 1H), 2.98 (s, 1H), 2.80 (s, 1H), 2.50 (s, 1H), 2.41 (s,3H), 2.20 (s, 3H), 1.91 (s, 2H), 1.76-1.69 (m, 1H), 1.48-1.45 (m, 1H).

Example 171 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-2′,3′-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-1,5-dione(Cpd. No. 171)

Synthesis of tert-butyl6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-2′(3′H)-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure E.

Synthesis of tert-butyl8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-2′(3′H)-carboxylate(5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-2′,3′-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-1,5-dione(Cpd. No. 171)

The synthesis of compound 171 is carried out as described above usingthe general protocol of Procedure F.

Example 172 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2′,3′-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-1,5-dione(Cpd. No. 172)

Synthesis of tert-butyl6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-chloro-1,5-dioxo-1,5-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-2′(3′H)-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-2′,3′-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-1,5-dione(Cpd. No. 172)

The synthesis of compound 172 is carried out as described above usingthe general protocol of Procedure F.

Example 173 Synthesis of8-chloro-6′-fluoro-6-(pyrimidin-4-ylamino)-2′,3′-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-1,5-dione(Cpd. No. 173)

Synthesis of tert-butyl6-bromo-8-chloro-6′-fluoro-1,5-dioxo-1,5-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-2′(3′H)-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure E.

Synthesis of tert-butyl8-chloro-6′-fluoro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-2′(3′H)-carboxylate(5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of8-chloro-6′-fluoro-6-(pyrimidin-4-ylamino)-2′,3′-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-1,5-dione(Cpd. No. 173)

The synthesis of compound 173 is carried out as described above usingthe general protocol of Procedure F.

Example 174 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6′-fluoro-2′,3′-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-1,5-dione(Cpd. No. 174)

Synthesis of tert-butyl6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-chloro-6′-fluoro-1,5-dioxo-1,5-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-2′(3′H)-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6′-fluoro-2′,3′-dihydro-1′H,2H-spiro[imidazo[1,5-a]pyridine-3,4′-isoquinoline]-1,5-dione(Cpd. No. 174)

The synthesis of compound 174 is carried out as described above usingthe general protocol of Procedure F.

Example 175 Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3′-indoline]-1,5-dione(Cpd. No. 175)

Synthesis of tert-butyl6-bromo-8-chloro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-indoline]-1′-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure E.

Synthesis of tert-butyl8-chloro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-indoline]-1′-carboxylate(5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of8-chloro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3′-indoline]-1,5-dione(Cpd. No. 175)

The synthesis of compound 175 is carried out as described above usingthe general protocol of Procedure F.

Example 176 Synthesis of8-chloro-5′-fluoro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3′-indoline]-1,5-dione(Cpd. No. 176)

Synthesis of tert-butyl6-bromo-8-chloro-5′-fluoro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-indoline]-1′-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure E.

Synthesis of tert-butyl8-chloro-5′-fluoro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-indoline]-1′-carboxylate(5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of8-chloro-5′-fluoro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3′-indoline]-1,5-dione(Cpd. No. 176)

The synthesis of compound 176 is carried out as described above usingthe general protocol of Procedure F.

Example 177 Synthesis of8-chloro-4′,4′-difluoro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 177)

Synthesis of tert-butyl6-bromo-8-chloro-4′,4′-difluoro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure E.

Synthesis of tert-butyl8-chloro-4′,4′-difluoro-1,5-dioxo-6-(pyrimidin-4-ylamino)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate(5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of8-chloro-4′,4′-difluoro-6-(pyrimidin-4-ylamino)-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 177)

The synthesis of compound 177 is carried out as described above usingthe general protocol of Procedure F.

Example 178 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-4′,4′-difluoro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 178)

Synthesis of tert-butyl6-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-8-chloro-4′,4′-difluoro-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-chloro-4′,4′-difluoro-2H-spiro[imidazo[1,5-a]pyridine-3,3′-piperidine]-1,5-dione(Cpd. No. 178)

The synthesis of compound 178 is carried out as described above usingthe general protocol of Procedure F.

Example 179 Synthesis of8′-chloro-2,2-dimethyl-6′-(pyrimidin-4-ylamino)-4,5-dihydro-2H,2′H-spiro[furan-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 179)

Synthesis of6′-bromo-8′-chloro-2,2-dimethyl-4,5-dihydro-2H,2′H-spiro[furan-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of8′-chloro-2,2-dimethyl-6′-(pyrimidin-4-ylamino)-4,5-dihydro-2H,2′H-spiro[furan-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 179)

The synthesis of compound 179 is carried out as described above usingthe general protocol of Procedure H.

Example 180 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-chloro-2,2-dimethyl-4,5-dihydro-2H,2′H-spiro[furan-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 180)

Synthesis of tert-butyl(6-((8′-chloro-2,2-dimethyl-1′,5′-dioxo-1′,4,5,5′-tetrahydro-2H,2′H-spiro[furan-3,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-chloro-2,2-dimethyl-4,5-dihydro-2H,2′H-spiro[furan-3,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 180)

The synthesis of compound 180 is carried out as described above usingthe general protocol of Procedure F.

Example 181 Synthesis of3,3-dimethyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-8-carbonitrile(Cpd. No. 181)

Synthesis of3,3-dimethyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-8-carbonitrile(Cpd. No. 181)

To a vial was added8-chloro-3,3-dimethyl-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-c]pyridine-1,5-dione(1, 1000 mg, 3.27 mmol), copper(I) cyanide (293 mg, 3.27 mmol) andsodium cyanide (160 mg, 3.27 mmol) in 1,4-dioxane (10 mL) at roomtemperature under argon. The reaction was purged with argon for 5-10min, followed by addition of tricyclohexylphosphine (92 mg, 0.33 mmol)and tris(dibenzylideneacetone)dipalladium(0) (299 mg, 0.33 mmol) underargon. The vial was then sealed and heated at 150° C. for 48 h. Aftercompletion the reaction was quenched with sat solution of potassiumpermanganate and extracted the crude compound with 10% methanol indichloromethane. The organic layer was concentrated to dryness and crudewas purified by flash column chromatography (silica gel 100-200 mesh)using 2% methanol in dichloromethane. The desired fractions wereconcentrated to dryness under vacuum to obtain3,3-dimethyl-1,5-dioxo-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-8-carbonitrile(Cpd. No. 181) as off white solid. Yield: 0.2 g, 20%; MS (ESI) m/z297.36 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.20 (s, 1H), 9.69 (s, 1H),8.90 (s, 1H), 8.85 (s, 1H), 8.44 (d, J=5.84 Hz, 1H), 7.44 (d, J=5.36 Hz,1H), 1.82 (s, 6H).

Example 182 Synthesis of6′-((2-aminopyridin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazine]-1′,5′-dione(Cpd. No. 182)

Synthesis of N, N-ditertbutoxycarbonyl-2-chloropyridin-4-amine (2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure J. Light brown solid; Yield: 5.3 g,70%; MS (ESI) m/z 329.21 [M+1]⁺.

Synthesis of N,N-di-tertbutoxycarbonyl(2-(cyclopropanecarboxamido))pyridin-4-amine (4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure B. Light brown solid; Yield: 2.5 g,51%; MS (ESI) m/z 378.61 [M+1]⁺.

Synthesis of N-(4-aminopyridin-2-yl)cyclopropanecarboxamidehydrochloride (5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 1.6 g,crude; MS (ESI) m/z 178.45 [M+1]⁺.

Synthesis of methyl5-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate(7)

The synthesis of intermediate 7 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 1.5 g, 48%; MS(ESI) m/z 344.05 [M+1]⁺.

Synthesis of5-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxamide(8)

The synthesis of intermediate 8 was carried out as described above usingthe general protocol of Procedure K. Yield: 600 mg, crude; MS (ESI) m/z329.06 [M+1]⁺.

Synthesis ofN-(4-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazin]-6′-yl)amino)pyridin-2-yl)cyclopropanecarboxamide(10)

5-((2-(cyclopropanecarboxamido)pyridin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxamide(8, 600 mg, 1.83 mmol) and cyclohexanone (538 mg, 5.48 mmol) werecharged in acetonitrile in a 20 mL microwave vial. Iron(III) chloride(889 mg, 1.83 mmol) was added and heated the reaction mixture at 80° C.for 16 h. On completion of the reaction, solvent was removed undervacuum and purified the compound by silica gel (200-400 mesh) columnchromatography eluting with 5% methanol in dichloromethane. Appropriatecolumn fractions were concentrated under reduced pressure to affordN-(4-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazin]-6′-yl)amino)pyridin-2-yl)cyclopropanecarboxamide(10, 100 mg, crude) as light brown crude solid which was directlyforwarded to next step. MS (ESI) m/z 409.43 [M+1]⁺.

Synthesis of6′-((2-aminopyridin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazine]-1′,5′-dione(Cpd. No. 182)

The synthesis of compound 182 was carried out as described above usingthe general protocol of Procedure I. Off white solid; Yield: 2 mg; MS(ESI) m/z 341.21[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.59 (s, 1H), 10.36(s, 1H), 10.18, (s, 1H), 8.09 (s, 1H), 7.79 (s, 1H), 7.77 (s, 2H), 7.27(s, 1H), 2.82-2.76 (m, 2H), 2.50 (s, 3H), 1.77-1.74 (m, 2H), 1.70-1.60(m, 3H), 1.55-1.52 (m, 2H), 1.23-1.19 (m, 1H).

Example 183 Synthesis of3′-amino-6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6′-fluoro-2′,3′-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-indene]-1,5-dione(Cpd. No. 183)

Synthesis of6-bromo-8-chloro-6′-fluoro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-indene]-1,3′,5(2′H)-trione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis ofN-(6-((8-chloro-6′-fluoro-1,3′,5-trioxo-1,2′,3′,5-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (5)

The synthesis of intermediate 5 is carried out as described above usingthe general protocol of Procedure H.

Synthesis ofN-(6-((3′-amino-8-chloro-6′-fluoro-1,5-dioxo-1,2′,3′,5-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(6)

To a solution ofN-(6-((3′-amino-8-chloro-6′-fluoro-1,5-dioxo-1,2′,3′,5-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(6, 1 g, 2.02 mmol) in 2-propanol (20 mL) was added ammonium acetate(0.47 g, 6.06 mmol) and sodium cyanoborohydride (1.02 g, 16.16 mmol).The reaction was stirred at 110° C. overnight. The resulting mixture wascooled to room temperature and poured into saturated aqueous sodiumbicarbonate solution. The mixture was extracted with dichloromethane.The organic layer was dried over magnesium sulfate, filtered andconcentrated. The crude was purified via column chromatography to affordN-(6-((3′-amino-8-chloro-6′-fluoro-1,5-dioxo-1,2′,3′,5-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-inden]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(6).

Synthesis of3′-amino-6-((6-aminopyrimidin-4-yl)amino)-8-chloro-6′-fluoro-2′,3′-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,1′-indene]-1,5-dione(Cpd. No. 183)

The synthesis of compound 183 is carried out as described above usingthe general protocol of Procedure I.

Example 184 Synthesis ofN-(6-((8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyanamide(Cpd. No. 184)

Synthesis of8-chloro-3-(3-chlorophenyl)-6-((6-fluoropyrimidin-4-yl)amino)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure H.

Synthesis ofN-(6-((8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyanamide(Cpd. No. 184)

To a solution of8-chloro-3-(3-chlorophenyl)-6-((6-fluoropyrimidin-4-yl)amino)-3-methyl-2,3-dihydroimidazo[1,5-a]pyridine-1,5-dione(3, 100 mg, 0.24 mmol) in N-methyl-2-pyrrolidinone (4 mL) was addedsodium hydrogencyanamide (46 mg, 0.72 mmol). The reaction was stirred at50° C. for 2 h. The resulting mixture was cooled to room temperature,poured into water and acidified to pH=5.5 with concentrated hydrochloricacid. The mixture was filtered. The solid crude was purified via HPLC toaffordN-(6-((8-chloro-3-(3-chlorophenyl)-3-methyl-1,5-dioxo-1,2,3,5-tetrahydroimidazo[1,5-a]pyridin-6-yl)amino)pyrimidin-4-yl)cyanamide(Cpd. No. 184).

Example 185 Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[bicyclo[2.2.1]heptane-7,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 185)

Synthesis of6′-bromo-8′-chloro-2′H-spiro[bicyclo[2.2.1]heptane-7,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure A.

Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[bicyclo[2.2.1]heptane-7,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 185)

The synthesis of compound 185 is carried out as described above usingthe general protocol of Procedure H.

Example 186 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[bicyclo[2.2.1]heptane-7,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 186)

Synthesis ofN-(6-((8′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[bicyclo[2.2.1]heptane-7,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[bicyclo[2.2.1]heptane-7,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 186)

The synthesis of compound 186 is carried out as described above usingthe general protocol of Procedure I.

Example 187 Synthesis of8-chloro-6-[(5-methoxypyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 187)

Synthesis of8-chloro-6-[(5-methoxypyrimidin-4-yl)amino]spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-1,5-dione(Cpd. No. 187)

The synthesis of compound 187 was carried out as described above usingthe general protocol of Procedure H. Grey solid; Yield: 0.052 g, 17%; MS(ESI) m/z 376.31 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 8.69(s, 1H), 8.64 (s, 1H), 8.53 (s, 1H), 8.29 (s, 1H), 4.01 (s, 3H),3.46-3.40 (m, 1H), 2.93-2.87 (m, 2H) 1.77-1.74 (m, 2H), 1.64-1.61 (m,3H), 1.55-1.52 (m, 2H), 1.23 (m, 1H).

Example 188 Synthesis of6′-((6-amino-5-ethylpyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 188)

Synthesis tert-butylN-tert-butoxycarbonyl-N-(6-chloro-5-ethyl-pyrimidin-4-yl)carbamate (2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure J. Light brown solid. Yield: 3.5 g,96%; MS (ESI) m/z 358.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s,1H), 2.70 (m, 3H), 1.4 (m, 18H), 1.20 (m, 3H).

Synthesis of tert-butylN-tert-butoxycarbonyl-N-[6[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]-5-ethyl-pyrimidin-4-yl]carbamate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure B. Yellow solid. Yield: 0.48 g, 42%;MS (ESI) m/z 589.45 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H),8.75 (s, 1H), 8.71 (s, 1H), 8.54 (s, 1H), 2.94 (m, 2H), 2.59 (m, 2H),1.74 (m, 2H), 1.65 (m, 2H), 1.57 (m, 2H), 1.14 (m, 18H), 1.25 (m, 1H),1.22 (m, 4H).

Synthesis of6′-((6-amino-5-ethylpyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 188)

The synthesis of compound 188 was carried out as described above usingthe general protocol of Procedure F. Yellow solid. Yield: 0.32 g, 94%;MS (ESI) m/z 389.06 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s, 1H),8.59 (s, 1H), 8.44-8.33 (m, 2H), 7.74 (brs, 2H), 2.93-2.90 (m, 2H), 2.66(m, 2H), 1.77-1.74 (m, 3H), 1.55-1.52 (m, 2H), 1.25-1.22 (m, 1H), 1.10(t, J=14.8 Hz, 3H).

Example 189 Synthesis of6′-((6-amino-5-isopropylpyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 189)

Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-chloro-5-isopropyl-pyrimidin-4-yl)carbamate(2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure J. White solid; Yield: 4.5 g, 90%; MS(ESI) m/z 372.3 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (s, 1H),3.32-3.20 (m, 1H), 1.52-1.20 (m, 24H).

Synthesis of tert-butylN-tert-butoxycarbonyl-N-[6[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]-5-isopropyl-pyrimidin-4-yl]carbamate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.41 g, 30%;MS (ESI) m/z 603.55 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H),8.75-8.72 (m, 2H), 8.67 (s, 1H), 3.32-3.19 (m, 1H), 2.94 (m, 2H), 1.74(m, 2H), 1.65 (m, 3H), 1.57 (m, 2H), 1.14 (m, 24H), 1.20-1.00 (m, 1H).

Synthesis of6′-((6-amino-5-isopropylpyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 189)

The synthesis of compound 189 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.30 g, 93%;MS (ESI) m/z 403.17 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.38 (s, 1H),9.51 (s, 1H), 8.45 (s, 2H), 7.69-7.68 (brs, 2H), 3.59-3.56 (m, 2H),2.93-2.87 (m, 2H), 1.77-1.74 (m, 2H), 1.68-1.65 (m, 3H), 1.56 (m, 2H),1.36 (m, 6H), 1.26 (m, 1H).

Example 190 Synthesis of8′-chloro-6′-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 190)

Synthesis of8′-chloro-6′-(7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 190)

The synthesis of compound 190 was carried out as described above usingthe general protocol of Procedure B. Yellow solid. Yield: 0.070 g, 7%;MS (ESI) m/z 370.09 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.66 (s, 1H),9.11 (s, 1H), 8.87 (s, 1H), 8.26 (s, 1H), 7.93 (d, J=3.56 Hz, 2H), 6.82(d, J=3.56 Hz, 2H), 2.94-2.89 (m, 2H), 1.74-1.57 (m, 7H), 1.23 (m, 1H).

Example 191 Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-2-(trifluoromethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 191)

Synthesis of6′-bromo-8′-chloro-2-(trifluoromethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 0.40 g,43%; MS (ESI) m/z 400.59 [M+1]⁺.

Synthesis of8′-chloro-6′-(pyrimidin-4-ylamino)-2-(trifluoromethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 191)

The synthesis of compound 191 was carried out as described above usingthe general protocol of Procedure B. White solid; Yield: 0.030 g, 8%; MS(ESI) m/z 346.80 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.53 (s, 1H), 9.66(s, 1H), 8.84 (d, J=9.6 Hz, 2H), 8.45 (d, J=5.92 Hz, 1H), 7.44 (d, J=4.8Hz, 1H), 4.03 (m, 1H), 2.88 (m, 1H), 2.04 (m, 1H), 1.80 (m, 3H), 1.67(m, 1H), 1.41 (s, 1H).

Example 192 Synthesis of8-chloro-3-methyl-3-(2-methylprop-1-enyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 192)

Synthesis of6-bromo-8-chloro-3-methyl-3-(2-methylprop-1-enyl)-2H-imidazo[1,5-a]pyridine-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Light brown thick liquid. Yield:1.5 g, 28%; MS (ESI) m/z 329 [M−1]⁻.

Synthesis of8-chloro-3-methyl-3-(2-methylprop-1-enyl)-6-(pyrimidin-4-ylamino)-2H-imidazo[1,5-a]pyridine-1,5-dione(Cpd. No. 192)

The synthesis of compound 192 was carried out as described above usingthe general protocol of Procedure H. White solid; Yield: 65 mg, 31%; MS(ESI) m/z 360.80 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (s, 1H), 9.62(s, 1H), 8.43 (d, J=5.6 Hz, 1H), 7.47 (d, J=4.8 Hz, 1H), 3.25-3.17 (m,2H), 280-2.78 (m, 2H), 2.39-2.33 (m, 2H), 2.24 (s, 3H), 1.50-1.47 (m,2H).

Example 193 Synthesis of6′-((6-amino-5-methylpyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 193)

Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-chloro-5-methyl-pyrimidin-4-yl)carbamate (2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure J. White solid; Yield: 1.1 g, 94%; MS(ESI) m/z 344.27 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 2.22(s, 1H), 1.38 (s, 18H).

Synthesis of tert-butylN-tert-butoxycarbonyl-N-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]-5-methyl-pyrimidin-4-yl]carbamate (4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.20 g, 35%;MS (ESI) m/z 575.32 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H),8.73 (s, 2H), 8.46 (s, 1H), 2.14 (s, 3H), 1.77-1.66 (m, 7H), 1.46 (m,18H), 1.20 (m, 1H).

Synthesis of6′-((6-amino-5-methylpyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 193)

The synthesis of compound 193 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.11 g, 80%;MS (ESI) m/z 375.26 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.41 (s, 1H),8.47 (s, 2H), 8.40 (s, 1H), 7.79 (brs, 2H), 2.93-2.87 (m, 1H), 2.07 (s,1H), 1.77-1.74 (m, 2H), 1.65-1.56 (m, 3H), 1.56-1.53 (m, 2H), 1.09 (m,1H).

Example 194 Synthesis of8′-chloro-6′-((5-ethylpyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 194)

Synthesis of8′-chloro-6′-((5-ethylpyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 194)

The synthesis of compound 194 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.026 g, 22%;MS (ESI) m/z 374.21 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.37 (s, 1H),8.78 (s, 1H), 8.72 (s, 1H), 8.39 (s, 1H), 8.34 (s, 1H), 2.95-2.89 (m,2H), 2.70-2.64 (m, 2H), 1.77-1.74 (m, 2H), 1.69-1.65 (m, 3H), 1.57-1.54(m, 2H), 1.26 (m, 4H).

Example 195 Synthesis of6′-((6-amino-5-methoxypyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 195)

Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-chloro-5-methoxy-pyrimidin-4-yl)carbamate (2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure J. Off white solid; Yield: 092 g, 59%;MS (ESI) m/z 360.12 [M+1]⁺; ¹H NMR (400 MHz; DMSO-d₆) δ 1.44 (s, 18H),3.92 (s, 3H), 8.64 (s, 1H).

Synthesis of tert-butylN-tert-butoxycarbonyl-N-[6-[(8-chloro-1,5-dioxo-spiro[2H-imidazo[1,5-a]pyridine-3,1′-cyclohexane]-6-yl)amino]-5-methoxy-pyrimidin-4-yl]carbamate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.14 g; 23%;MS (ESI) m/z 591.23 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H),8.78 (s, 1H), 8.67 (s, 1H), 8.6 (s, 1H), 3.87 (s, 3H), 2.92 (m, 2H),1.81-1.54 (m, 7H), 1.40 (s, 18H), 1.23 (m, 1H)

Synthesis of6′-((6-amino-5-methoxypyrimidin-4-yl)amino)-8′-chloro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 195)

The synthesis of compound 195 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 0.075 g,80%; MS (ESI) m/z 391.12 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.35 (s,1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.19 (s, 1H), 7.33 (brs, 2H), 3.74 (s,3H), 2.91 (m, 2H), 1.76-1.52 (m, 7H), 1.26 (m, 1H).

Example 196 Synthesis of8′-chloro-6′-((5-ethoxypyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 196)

Synthesis of8′-chloro-6′-((5-ethoxypyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 196)

The synthesis of compound 196 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.055 g, 20%;MS (ESI) m/z 390.13 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.42 (s, 1H),8.82 (s, 1H), 8.75 (s, 1H), 8.62 (s, 1H), 8.33 (s, 1H), 4.30 (q, J=6.96Hz, 2H), 2.90 (m, 2H), 1.74-1.53 (m, 7H), 1.43 (t, J=6.96 Hz, 3H), 1.25(m, 1H).

Example 197 Synthesis of8′-chloro-6′-((5-isopropoxypyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 197)

Synthesis of N,N-di-boc-4-aminopyrimidin-5-ol (2)

The synthesis of intermediate 2 was carried out as described above usingthe general protocol of Procedure J. Brown solid; Yield: 1.2 g, 86%; MS(ESI) m/z 312.15 [M+1]⁺; ¹H NMR (400 MHz; CDCl₃) δ 8.96 (s, 1H), 8.76(s, 1H), 1.42 (s, 18H).

Synthesis of N,N-di-boc-5-isopropoxypyrimidin-4-amine (3)

To a solution of N,N-di-boc-4-aminopyrimidin-5-ol (2, 1.0 g, 3.21 mmol)in dimethylformamide (15 mL), potassium carbonate (1.11 g, 8.03 mmol)was added followed by addition of 2-iodo propane (1.64 g, 9.64 mmol).The reaction mixture was stirred at 60° C. for 3 h. The reaction mixturewas cooled, diluted with ethyl acetate (50 mL) and washed with coldwater (3×20 mL) and brine, dried over sodium sulfate and concentratedunder reduced pressure to afford N,N-diboc-5-isopropoxypyrimidin-4-amine(3) as white solid. Yield: 1.1 g, 97%; MS (ESI) m/z 354.20 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.70 (s, 1H), 4.89 (m, 1H), 1.37(s, 18H), 1.27 (d, J=6.0 Hz, 6H).

Synthesis of 5-isopropoxypyrimidin-4-amine hydrochloride (4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 0.55 g,93%; MS (ESI) m/z 154.09 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 14.32 (brs,1H), 9.10-8.60 (m, 2H), 8.48 (s, 1H), 8.31 (brs, 1H), 8.06 (s, 1H), 4.72(m, 1H), 1.32 (d, J=6.0 Hz, 6H)

Synthesis of8′-chloro-6′-((5-isopropoxypyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 197)

The synthesis of compound 197 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.22 g, 61%;MS (ESI) m/z 404.14 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.4 (s, 1H),8.71 (s, 2H), 8.56 (s, 1H), 8.34 (s, 1H), 4.87 (m, 1H), 2.92 (m, 2H),1.77-1.53 (m, 7H), 1.37 (d, J=6.0 Hz, 6H), 1.23 (m, 1H).

Example 198 Synthesis of8′-chloro-2′-cyclopentyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 198)

Synthesis of8′-chloro-2′-cyclopentyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 198)

In a vial8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(0.5 g, 1.44 mmol), bromocyclopentane (0.26 g, 1.73 mmol) and potassiumphosphate (0.49 g, 3.62 mmol) were taken in 1,4-dioxane (10 mL). Thereaction mixture was purged with argon for 10 min and copper(I) iodide(0.027 g, 0.14 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (0.041g, 0.14 mmol) were added and purging was continued for another 10 min.The reaction was sealed and heated at 110° C. for 24 h. Aftercompletion, the reaction was diluted with 5% methanol in dichloromethane(300 mL) and filtered through a celite bed. The filtrate wasconcentrated. The crude compound was purified by column chromatographyusing neutral alumina and the compound was eluted with dichloromethane.The solvent was removed under reduced pressure to get solid which wasdried under high vacuum to afford8′-chloro-2′-cyclopentyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 198) as an off white solid. Yield: 0.035 g, 6%; MS (ESI) m/z414.14 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H), 8.81 (s, 1H),8.77 (s, 1H), 8.40 (d, J=5.84 Hz, 1H), 7.41 (d, J=5.32 Hz, 1H), 5.33 (s,1H), 2.93 (m, 2H), 1.92 (m, 12H), 1.62 (m, 2H), 1.37 (m, 2H).

Example 199 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-5′-thioxo-2′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one(Cpd. No. 199)

Synthesis of n-butyl5-((6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylicacid (4)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure I.

Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylicacid (5)

To a solution of5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylicacid (4, 0.5 g, 1.91 mmol) in pyridine (10 mL) is added phosphoruspentasulfide (1.27 g, 5.73 mmol). The reaction is refluxed overnight.The resulting mixture is cooled to room temperature and concentrated.The crude is purified via column chromatography to afford5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylicacid (5).

Synthesis of methyl5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylate(6)

To a solution of5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylicacid (5, 0.5 g, 1.72 mmol) in tetrahydrofuran (10 mL) and methanol isadded (trimethylsilyl)diazomethane (2 M in hexanes, 1.29 mL, 2.58 mmol).The reaction is stirred at room temperature for 1 h. The resultingmixture is concentrated and purified via column chromatography to affordmethyl5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxylate(6).

Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-methyl-6-thioxo-1,6-dihydropyridine-2-carboxamide(7)

The synthesis of intermediate 7 is carried out as described above usingthe general protocol of Procedure K.

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-5′-thioxo-2′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one(Cpd. No. 199)

The synthesis of compound 199 is carried out as described above usingthe general protocol of Procedure A.

Example 200 Synthesis of6′-((6-aminopyrimidin-4-yl)(methyl)amino)-8′-chloro-2′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 200)

Synthesis of tert-butyl(6-(cyclopropanecarboxamido)pyrimidin-4-yl)(methyl)carbamate (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 2.5 g, 80%; MS(ESI) m/z 293.51 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.06 (s, 1H), 8.63(s, 1H), 8.59 (s, 1H), 2.05-1.99 (m, 1H), 1.49 (s, 9H), 0.85-0.83 (m,4H).

Synthesis of N-(6-(methylamino)pyrimidin-4-yl)cyclopropanecarboxamidehydrochloride (4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure F. White solid; Yield: 1.4 g, 90%; MS(ESI) m/z 193.30 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 11.87 (brs, 1H),9.10 (brs, 1H), 8.45 (s, 1H), 7.05 (brs, 1H), 2.91 (s, 3H), 2.01 (m,1H), 0.93-0.89 (m, 4H).

Synthesis ofN-(6-((8′-chloro-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)(methyl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 120 mg, 18%;MS (ESI) m/z 427.01 [M−1]⁻.

Synthesis of6′-((6-aminopyrimidin-4-yl)(methyl)amino)-8′-chloro-2′H-spiro[cyclopentane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 200)

The synthesis of compound 200 was carried out as described above usingthe general protocol of Procedure I. Light brown solid; Yield: 27 mg,32%; MS (ESI) m/z 361.12 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.46 (s,1H), 8.29 (s, 1H), 8.04 (s, 1H), 7.59 (brs, 2H), 5.72 (s, 1H), 3.27 (s,3H), 2.76-2.69 (m, 2H), 1.91-1.84 (m, 2H), 1.82-1.79 (m, 2H), 1.74-1.69(m, 2H).

Example 201 Synthesis of6′-(pyrimidin-4-ylamino)-8′-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 201)

Synthesis of8′-(3,6-dihydro-2H-pyran-4-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

A vial was charged with8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 0.50 g, 1.44 mmol) and2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2, 0.36 g, 1.73 mmol) in 1,4-dioxane (10 mL). Sodium carbonate (0.46 g,4.33 mmol) was added followed by water (1.44 mL) and purged the mixturewith argon for 10 min.[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (0.11 g, 0.144 mmol) was then added and purging wascontinued for 5 more min. The reaction was sealed and heated at 110° C.for 16 h. After completion of reaction by TLC and LCMS. Water (100 mL)was added and extracted with 10% methanol in dichloromethane (3×150 mL).The organics were washed with brine (1×100 mL). The organics were thenseparated and dried (sodium sulfate) before concentration to dryness.The crude was then purified by flash column chromatography eluting with2-3% methanol in dichloromethane. The desired fractions wereconcentrated to dryness under vacuum to afford8′-(3,6-dihydro-2H-pyran-4-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3) as an off white solid. Yield: 0.35 g, 61%; MS (ESI) m/z 394 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s, 1H), 9.41 (s, 1H), 8.78 (s, 1H),8.61 (s, 1H), 8.43 (d, J=6.08 Hz, 1H), 7.44 (d, J=5.72 Hz, 1H), 5.75 (s,1H), 4.18 (s, 2H), 3.79 (s, 2H), 3.05 (m, 2H), 2.45 (m, 2H), 1.84 (m,6H), 1.56 (s, 2H).

Synthesis of6′-(pyrimidin-4-ylamino)-8′-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 201)

A double neck round bottom flask was charged with8′-(3,6-dihydro-2H-pyran-4-yl)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3, 0.22 g, 0.57 mmol) in methanol (10 mL) and tetrahydrofuran (10 mL).Palladium on carbon (0.10 g) was added followed by ammonium hydroxide(1.0 mL) under nitrogen atmosphere. The reaction was filled withhydrogen and stirred at room temperature for 3 d. After completion ofreaction monitored by TLC and LCMS, the reaction mass was diluted with5% methanol in dichloromethane (100 mL) and passed through celite bedand washed with 10% methanol/dichloromethane (3×50 mL). Solvent wasremoved under vacuum and crude material was purified by prep HPLC toafford6′-(pyrimidin-4-ylamino)-8′-(tetrahydro-2H-pyran-4-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 201) as a white solid. Yield: 0.11 g, 49%; MS (ESI) m/z 396.4[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (6, 1H), 9.40 (s, 1H), 8.85(s, 1H), 8.81 (s, 1H), 8.38 (d, J=5.88 Hz, 1H), 7.37 (d, J=5.88 Hz, 1H),4.20 (m, 1H), 3.96 (m, 2H), 3.42 (t, J=11.3 Hz, 2H), 3.01 (m, 2H), 1.70(m, 9H), 1.58 (m, 2H), 1.22 (m, 1H).

Example 202 Synthesis of6′-((6-amino-5-hydroxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 202)

Synthesis of tert-butylN-tert-butoxycarbonyl-N-(5-methoxy-6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.45 g, 64%;MS (ESI) m/z 571.15 [M+1]⁺.

Synthesis of6′-((6-amino-5-hydroxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 202)

A flask was charged with tert-butylN-tert-butoxycarbonyl-N-(5-methoxy-6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate(3, 0.40 g, 0.70 mmol) and dichloromethane (20 mL) was added and mixturewas cooled to −20° C. boron tribromide (0.87 g, 3.50 mmol) was thenadded to the mixture drop wise. The reaction mass was stirred at roomtemperature overnight. After completion, water was added to the reactionmixture and quenched with saturated aqueous solution of sodiumbicarbonate till pH 8. Yellow solid was precipitated out, filtered andwashed with water (20 mL) followed by diethyl ether then finally driedunder high vacuum to afford6′-((6-amino-5-hydroxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 202) as yellow solid. Yield: 0.085 g, 34%; MS (ESI) m/z 357.16[M+1]⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.15 (brs, 1H), 8.50(s, 1H), 8.40 (m, 1H), 8.08 (s, 1H), 6.65 (brs, 2H), 3.00-2.94 (m, 2H),2.44 (s, 3H), 1.73-1.62 (m, 5H), 1.46-1.43 (m, 2H), 1.24-1.21 (m, 1H).

Example 203 Synthesis of6′-((6-amino-2-hydroxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 203)

Synthesis of6′-((6-(di-(tert-butoxycarbonyl)-amino)-2-methoxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.77 g, 51%;MS (ESI) m/z 571.21 [M+1]⁺.

Synthesis of6′-((6-amino-2-hydroxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 203)

To a stirred solution of6′-((6-(di-(tert-butoxycarbonyl)-amino)-2-methoxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3, 0.77 g, 1.35 mmol) in dichloromethane (15 mL) at −20° C., borontribromide (1 mL) was added. The mixture was stirred for another 20 minat the same temperature and then stirred for 48 h at room temperaturewhen TLC showed complete conversion of starting material. The mixturewas quenched by addition of methanol (2 mL) and the solvent was removedunder reduced pressure to afford the crude. The crude was purified bywashing with methanol (5 mL), dichloromethane (5 mL) and pentane (25 mL)to afford6′-((6-amino-2-hydroxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 203) as pale yellow solid. Yield: 0.28 g, 58%; MS (ESI) m/z357.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (brs, 2H), 8.58 (brs,1H), 8.47 (brs, 1H), 6.46 (brs, 2H), 5.39 (brs, 1H), 3.05-2.92 (m, 2H),2.40 (s, 3H), 1.80-1.54 (m, 6H), 1.48-1.50 (m, 2H), 1.28-1.16 (m, 1H).

Example 204 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-2-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 204)

Synthesis of6′-bromo-2-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Pale yellow solid; Yield: 1.3 g,62%; MS (ESI) m/z 326.97 [M+1]⁺.

Synthesis of tert-butyl(6-((2-hydroxy-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Pale yellow solid; Yield: 1.1 g,79%; MS (ESI) m/z 457.34 [M+1]⁺.

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-2-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 204)

The synthesis of compound 204 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.21 g, 25%;MS (ESI) m/z 357.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.55 (s, 1H),8.60 (brs, 1H), 8.30 (s, 1H), 8.19 (brs, 1H), 6.62 (brs, 2H), 6.17 (s,1H), 5.00-4.95 (m, 1H), 4.70-4.62 (m, 1H), 3.10-3.00 (m, 1H), 1.82-1.48(m, 6H), 1.38-1.28 (m, 1H).

Example 205 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-3-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 205)

Synthesis of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,3,5′-trione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 1.6 g, 22%;MS (ESI) m/z 329.9 [M+1]⁺.

Synthesis ofN-(6-((8′-methyl-1′,3,5′-trioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.40 g,51%; MS (ESI) m/z 457.31 [M+1]⁺.

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-3-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 205)

A flask containing tetrahydrofuran and ethanol (1:1, 20 mL) was chargedwithN-(6-((8′-methyl-1′,3,5′-trioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(5, 0.4 g, 0.9 mmol) and 3 M potassium hydroxide solution (8.0 mL) wasadded to the above reaction. The reaction was stirred at roomtemperature for 18 h. After complete hydrolysis, sodium borohydride(0.18 g, 0.4 mmol) was added to the above reaction at room temperature.The reaction mass was stirred for 2 h when TLC showed completion ofstarting material. The solvents were removed under reduced pressure andcrude was dissolved in 10% methanol in dichloromethane and neutralizedwith 10% citric acid. The organic layer was separated and dried oversodium sulfate, filtered and concentrated to obtain solid. The solid wasfiltered and washed with methanol (5 mL) and pentane (20 mL) and driedunder high vacuum to afford6′-((6-aminopyrimidin-4-yl)amino)-4-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 205) as yellow solid as a mixture of diastereomers. Yield:0.045 g, 13%; MS (ESI) m/z 357.19 [M+1]⁺; ¹H NMR: (400 MHz, DMSO-d₆) δ9.89 & 8.48 (2 s, 1H each, isomer A & B), 8.59 & 8.57 (2 s, 1H each,isomer A & B), 8.42 (brs, 1H), 8.16 (brs, 1H), 6.52 (brs, 2H), 6.16(brs, 1H), 5.16 & 4.85 (2 s, 1H each, isomer A & B), 4.22 and 3.73 (2 m,1H each, isomer A & B), 2.99 & 2.88 (2 m, 2H each, isomer A & B), 2.42(s, 3H), 1.98-1.11 (m, 6H).

Example 206 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-4-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 206)

Synthesis of6′-bromo-4-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 1.0 g, 35%;MS (ESI) m/z 326.91 [M+1]⁺.

Synthesis of tert-butyl(6-((4-hydroxy-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.45 g,81%; MS (ESI) m/z 457.31 [M+1]⁺.

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-4-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 206)

The synthesis of compound 206 was carried out as described above usingthe general protocol of Procedure F. Yellow solid as a mixture ofdiastereomers; Yield: 0.049 g, 12%; MS (ESI) m/z 357.09 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 10.04 & 9.97 (2 s, 1H each, isomer A & B), 8.58 &8.56 (2 s, 1H each, isomer A & B), 8.38 & 8.35 (2 s, 1H each, isomer A &B), 8.16 (s, 1H), 6.51 (brs, 2H), 6.15 & 6.14 (2 s, 1H each, isomer A &B), 4.78 & 4.46 (2 brs, 1H each, isomer A & B), 3.86 & 3.53 (2 m, 1Heach, isomer A & B), 3.41 & 3.09 (2 m, 2H each, isomer A & B), 2.42 (s,3H), 1.85-1.56 (m, 4H), 143 & 1.17 (2 m, 2H each, isomer A & B).

Example 207 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-(hydroxymethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 207)

Synthesis ofN-(6-((1′,5′-dioxo-8′-vinyl-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure G. brown solid; Yield: 1.5 g, 51%; MS(ESI) m/z 421.22 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.88 (s, 1H),10.25 (s, 1H), 9.20 (s, 1H), 8.99 (s, 1H), 8.56 (s, 1H), 7.92-7.84 (m,2H), 5.70 (d, J=17.6 Hz, 1H), 5.34 (d, J=11.6 Hz, 1H), 3.32 (m, 1H),2.99-2.93 (m, 2H), 2.05-1.98 (m, 2H), 1.72-1.66 (m, 5H), 1.43-1.40 (m,2H), 1.34-1.16 (m, 1H), 0.85 (m, 4H).

Synthesis ofN-(6-((8′-formyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(4)

To a stirred solution ofN-(6-((1′,5′-dioxo-8′-vinyl-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3, 2.0 g, 4.75 mmol) and sodium periodate (3.05 g, 14.26 mmol) indioxane and water (2:1, 30 mL), a solution of osmium tetroxide inbutanol (0.60 g, 2.38 mmol) was added drop wise at 0° C. The reactionmass was stirred at room temperature overnight. After TLC showedcompletion, the solvent was evaporated under reduced pressure and water(100 mL) was added. The mixture was extracted with 10% methanol indichloromethane (2×50 mL). The organics were then separated and dried(magnesium sulfate) and concentrated to dryness under vacuum to affordN-(6-((8′-formyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(4) as brown solid. Yield: 1.2 g, 60%; MS (ESI) m/z 423.26 [M+1]⁺.

Synthesis ofN-(6-((8′-(hydroxymethyl)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(5)

To a stirred solution ofN-(6-((8′-formyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(1.2 g, 2.85 mmol) in methanol/tetrahydrofuran (1:2, 30 mL), sodiumborohydride was added portion wise at 0° C. The reaction mass wasstirred at 0° C. for 2 h. After completion, the reaction mixture wasdiluted with water (100 mL) and the mixture was extracted with 10%methanol in dichloromethane (2×50 mL). The organics were then separatedand dried (magnesium sulfate) and concentrated to dryness under vacuumto affordN-(6-((8′-(hydroxymethyl)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(5) as brown solid. Yield: 0.7 g, 62%; MS (ESI) m/z 423.43 [M−1]⁻; ¹HNMR (400 MHz, DMSO-d₆) δ 10.86 (s, 1H), 10.24-10.18 (m, 1H), 8.71-8.62(m, 1H), 8.56-8.52 (m, 1H), 7.84 (s, 1H), 6.13-5.33 (m, 1H), 4.47-4.33(m, 3H), 3.16-2.84 (m, 4H), 2.01-1.86 (m, 2H), 1.72-1.66 (m, 5H),1.43-1.40 (m, 2H), 1.34-1.16 (m, 1H).

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-(hydroxymethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 207)

The synthesis of compound 207 was carried out as described above usingthe general protocol of Procedure I. Brown solid; Yield: 0.18 g, 29%; MS(ESI) m/z 357.35 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (s, 1H), 9.23(m, 1H), 8.47 (m, 1H), 8.33 (s, 1H), 7.25 (brs, 2H), 6.27 (s, 1H), 5.18(brs, 1H), 4.81 (s, 2H), 3.01 (m, 2H), 1.73-1.62 (m, 5H), 1.46-1.44 (m,2H), 1.23 (m, 1H).

Example 208 Synthesis of6′-((5-cyclopropylpyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 208)

Synthesis of 5-cyclopropylpyrimidin-4-amine (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure G. Brown solid; Yield: 0.41 g, 78%; MS(ESI) m/z 136.08 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (s, 1H), 7.81(s, 1H), 6.75 (brs, 2H), 1.57-1.53 (m, 1H), 0.86-0.82 (m, 2H), 0.56-0.53(m, 2H).

Synthesis of6′-((5-cyclopropylpyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1,5′-dione(Cpd. No. 208)

The synthesis of compound 208 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.14 g,24%; MS (ESI) m/z 366.20 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (s,1H), 8.88 (s, 1H), 8.72 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 3.01-2.96(m, 2H), 2.5 (s, 3H), 1.84-1.59 (m, 6H), 1.48-1.45 (m, 2H), 1.30-1.27(m, 1H), 1.05-1.01 (m, 2H), 0.73-0.69 (m, 2H).

Example 209 Synthesis of8′-methyl-6′-(pyrimidin-4-yloxy)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 209)

Synthesis of6′-((4-methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2)

To a solution of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2 g, 6.43 mmol) in dimethylformamide (30 mL) is added sodium hydride(0.46 g, 19.29 mmol) and 4-methoxybenzyl alcohol (3.19 mL, 25.72 mmol).The reaction is stirred at room temperature overnight. The resultingmixture is poured into iced water and extracted with dichloromethane.The organic layer is dried over magnesium sulfate, filtered andconcentrated. The crude is purified via column chromatography to afford6′-((4-methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2).

Synthesis of6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

To a solution of6′-((4-methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2, 1.5 g, 4.07 mmol) in dichloromethane (20 mL) is added2,3-dichloro-5,6-dicyano-p-benzoquinone (1.38 g, 6.10 mmol). Thereaction is stirred at room temperature for 2 h. The resulting mixtureis concentrated and purified via column chromatography to afford6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3).

Synthesis of8′-methyl-6′-(pyrimidin-4-yloxy)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 209)

To a solution of6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3, 1 g, 4.03 mmol) in dimethylacetamide (20 mL) is added potassiumcarbonate (1.67 g, 12.09 mmol) and 4-bromopyrimidine (4, 0.77 g, 4.84mmol). The reaction is stirred at 130° C. overnight. The resultingmixture is cooled to room temperature, poured into water and extractedwith dichloromethane. The organic layer is dried over magnesium sulfate,filtered and concentrated. The crude is purified via columnchromatography to afford8′-methyl-6′-(pyrimidin-4-yloxy)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 209).

Example 210 Synthesis of8′-methyl-6′-(pyrimidin-4-ylthio)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 210)

Synthesis of6′-((4-methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

To a solution of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 2 g, 6.43 mmol) in dimethylformamide (30 mL) is added cesiumcarbonate (6.28 g, 19.29 mmol) and (4-methoxyphenyl)methanethiol (2,1.19 g, 7.72 mmol). The reaction is stirred at 100° C. overnight. Theresulting mixture is cooled to room temperature, poured into water andextracted with dichloromethane. The organic layer is dried overmagnesium sulfate, filtered and concentrated. The crude is purified viacolumn chromatography to afford6′-((4-methoxybenzyl)thio)-8′-methyl-TH-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3).

Synthesis of6′-mercapto-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4)

To a solution of6′-((4-methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3, 3.3 g, 8.58 mmol) in chloroform (40 mL) is added methanesulfonicacid (3 mL, 46. 23 mmol). The reaction is stirred at 50° C. overnight.The resulting mixture is cooled to room temperature, poured into waterand extracted with dichloromethane. The organic layer is dried overmagnesium sulfate, filtered and concentrated. The crude is purified viacolumn chromatography to afford6′-mercapto-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4).

Synthesis of6′-((2-chloropyrimidin-4-yl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(6)

To a solution of6′-mercapto-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4, 0.50 g, 1.89 mmol) in 2-propanol (10 mL) is addedN,N-diisopropylethylamine (0.99 mL, 5.67 mmol) and2,4-dichloropyrimidine (5, 0.34 g, 2.27 mmol). The reaction is stirredat 70° C. overnight. The resulting mixture is cooled to roomtemperature, poured into water and extracted with dichloromethane. Theorganic layer is dried over magnesium sulfate, filtered andconcentrated. The crude is purified via column chromatography to afford6′-((2-chloropyrimidin-4-yl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(6).

Synthesis of8′-methyl-6′-(pyrimidin-4-ylthio)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 210)

To a solution of6′-((2-chloropyrimidin-4-yl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(6, 0.3 g, 0.80 mmol) in acetic acid (4 mL) is added zinc copper couple(0.5 g). The reaction is stirred at reflux for 4 h. The resultingmixture is cooled to room temperature, filtered and concentrated. Thecrude is purified via column chromatography to afford8′-methyl-6′-(pyrimidin-4-ylthio)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 210).

Example 211 Synthesis of8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 211)

Synthesis of8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 211)

To a solution of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2, 0.3 g, 0.96 mmol) in tetrahydrofuran (25 mL), n-butyllithium (0.58g, 2.89 mmol) was added at −78° C. The reaction mixture was stirred for30 min. To the mixture N-methoxy-N-methylpyrimidine-4-carboxamide (1,0.25 g, 1.44 mmol) was added at −78° C. and then the mixture was stirredat room temperature for 16 h. After completion, the reaction wasquenched with aqueous solution of ammonium chloride (50 mL) andextracted with dichloromethane (2×50 mL). The organic layer wasseparated and washed with brine (25 mL) and the solvent was evaporatedunder reduced pressure. The crude was purified by silica gel (220-400mesh) column chromatography using 0.5% methanol in dichloromethane aseluent. The fractions were concentrated to afford8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dioneas yellow solid. Yield: 0.001 g, 3.0%; MS (ESI) m/z 339.13 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.58 (s, 1H), 9.26 (s, 1H), 9.07 (d, J=5.08Hz, 1H), 9.97 (s, 1H), 7.83 (d, J=5.2 Hz, 1H), 2.85-2.75 (m, 2H), 2.45(s, 3H), 1.68-162 (m, 2H), 1.60-1.53 (m, 3H), 1.46-1.43 (m, 2H),1.10-1.09 (m, 1H).

Example 212 Synthesis of8′-methyl-6′-(pyrimidin-4-ylmethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 212)

Synthesis of8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

To a solution of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2, 2 g, 6.43 mmol) in tetrahydrofuran (30 mL) at −78° C. is addedn-butyllithium (1.6 M in hexanes, 12.06 mL, 19.29 mmol) dropwise,followed by N-methoxy-N-methylpyrimidine-4-carboxamide (1, 1.29 g, 7.72mmol). The reaction is slowly warmed to room temperature and stirred for4 h. The reaction is quenched via the slow addition of water. Themixture is warmed to room temperature and extracted with ethyl acetate.The organic layer is dried over magnesium sulfate, filtered andconcentrated. The crude is purified via column chromatography to afford8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3).

Synthesis of6′-(hydrazono(pyrimidin-4-yl)methyl)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (4)

To a solution of8′-methyl-6′-(pyrimidine-4-carbonyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3, 0.7 g, 2.07 mmol) in ethanol (4 mL), acetic acid (4 mL) and water (4mL) is added hydrazine hydrate (0.13 g, 4.14 mmol). The reaction isstirred at 80° C. overnight. The reaction is cooled to room temperatureand concentrated. The crude is resuspended in dichloromethane and iswashed with saturated aqueous sodium bicarbonate solution. The organiclayer is dried over magnesium sulfate, filtered and concentrated. Thecrude is purified via column chromatography to afford6′-(hydrazono(pyrimidin-4-yl)methyl)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4).

Synthesis of8′-methyl-6′-(pyrimidin-4-ylmethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 212)

To a solution of6′-(hydrazono(pyrimidin-4-yl)methyl)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4, 100 mg, 0.28 mmol) in toluene (4 mL) is added potassiumtert-butoxide (94 mg, 0.84 mmol). The reaction is refluxed overnight.The resulting mixture is cooled to room temperature, diluted withdichloromethane and is washed with 1 M ammonium chloride solution. Theorganic layer is dried over magnesium sulfate, filtered andconcentrated. The crude is purified via HPLC to afford8′-methyl-6′-(pyrimidin-4-ylmethyl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 212).

Example 213 Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxamide(Cpd. No. 213)

Synthesis of ethyl5-bromo-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxylate (3)

To a solution of ethyl5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (1, 1.0 g, 3.56mmol) and 1-iodo-2-methylpropane (2, 1.31 g, 7.13 mmol) indimethylformamide (12 mL) in a vial, potassium carbonate (261 mg, 1.89mmol) was added and the mixture was stirred at room temperature for 16h. After completion, the reaction mass was diluted with water (50 mL)and extracted with ethyl acetate (2×50 mL). Combined organic layer waswashed with water, brine, dried over anhydrous sodium sulfate andconcentrated under vacuum. The crude was purified by silica gel (220-400mesh) column chromatography using 50% ethyl acetate in hexane as aneluent to afford ethyl5-bromo-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxylate (3)as light yellow solid. Yield: 0.70 g, 58%; MS (ESI) m/z 336.3 [M+1]⁺.

Synthesis of ethyl5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxylate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.36 g,40%; MS (ESI) m/z 466.2 [M+1]⁺.

Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxamide(Cpd. No. 213)

To a solution of ethyl5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxylate(5, 300 mg, 0.64 mmol) in methanol (20 mL) was added magnesium nitride(3.25 g, 3.21 mmol) and the reaction was refluxed for 16 h. Aftercompletion, solvent was removed under reduced pressure and the resultingresidue was stirred in 2 N hydrochloric acid for 10 m. The reactionmixture was filtered and the obtained solid was dried under reducedpressure. The crude was purified by prep purification, to afford5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-isobutyl-6-oxo-1,6-dihydropyridine-2-carboxamide(Cpd. No. 213) as an off white solid. Yield: 70 mg, 32%; MS (ESI) m/z336.99 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 8.33 (s, 1H),8.27 (s, 1H), 7.87 (s, 1H), 7.59-7.54 (m, 3H), 6.05 (s, 1H), 4.17-4.16(d, J=6.8 Hz, 2H), 2.08-2.01 (m, 1H), 0.95-0.93 (d, J=6.8 Hz, 6H).

Example 214 Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide(Cpd. No. 214)

Synthesis of ethyl5-bromo-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate(2)

A solution of ethyl5-bromo-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxylate (3.0 g, 10.7mmol), 4-methoxybenzyl chloride (4.19, 26.74 mmol) and potassiumcarbonate (4.43 g, 32.09 mmol) in dimethylformamide (40 ml) was stirredat room temperature for 16 h. After completion, the reaction mixture wasdiluted with cold water (20 mL) and extracted with ethyl acetate (3×30mL). The organic layer was again washed with brine, separated, driedover Sodium sulfate, filtered and concentrated under reduced pressure.The residue was finally purified by flash column chromatography toafford ethyl5-bromo-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate(2) as off white solid. Yield: 1.2 g, 28%; MS (ESI) m/z 399.99 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.11 (d, J=8.64 Hz, 2H), 6.89(d, J=8.6 Hz, 2H), 5.11 (s, 2H), 4.27 (q, J=7.12 Hz, 2H), 3.72 (s, 3H),1.13 (t, J=7.12 Hz, 3H).

Synthesis of ethyl5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure H. Brown solid; Yield: 0.70 g, 44%; MS(ESI) m/z 530.17 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.04 (s, 1H), 9.49(s, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 7.76 (s, 1H), 7.11 (d, J=8.2 Hz,2H), 6.89 (d, J=8.44 Hz, 2H), 5.21 (s, 2H), 4.23 (q, J=6.92 Hz, 2H),3.72 (s, 3H), 1.48 (s, 9H), 1.13 (t, J=7.04 Hz, 3H).

Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid (5)

Sodium hydroxide (0.26 g, 6.6 mmol) was added to a suspension of ethyl5-((6-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylate(0.70 g, 1.32 mmol) in methanol/tetrahydrofuran/water (2:1:1, 30 mL).The mixture was stirred at 80° C. for 16 h. After completion, thesolvent was evaporated to dryness under reduced pressure. The crude wasdiluted with 1 N hydrochloric acid. The precipitate obtained wascollected by filtration, dried, washed with pentane and dried further toafford5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid (5) as brown solid. Yield: 0.45 g, 85%; MS (ESI) m/z 402.09 [M+1]⁺;¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H),7.67 (brs, 2H), 7.19 (d, J=8.16 Hz, 2H), 6.87 (d, J=8.12 Hz, 2H), 6.39(s, 1H), 5.18 (s, 2H), 3.71 (s, 3H).

Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxamide(6)

To a solution of5-((6-aminopyrimidin-4-yl)amino)-3-chloro-1-(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxylicacid (5, 0.40 g, 0.99 mmol) and 4-methoxybenzylamine (0.16 g, 1.19 mmol)in dimethylformamide (20 mL) was added N,N-diisopropylethylamine (0.39g, 2.99 mmol) and HATU (0.57 g, 1.99 mmol) at room temperature. Thereaction mixture was stirred for 40 h. Progress of the reaction wasmonitored by LCMS. To the reaction mixture was added tetrahydrofuran (20mL) and the reaction was refluxed for 7 h. After completion, thereaction was diluted with water (20 mL) and extracted with 10% methanolin dichloromethane (2×30 mL). The combined organic layer was dried oversodium sulfate, filtered and evaporated under reduced pressure to obtainthe crude. The crude was purified by flash column chromatography elutingat 1% methanol in dichloromethane. The best fractions were concentratedto afford5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxamide(6) as yellow solid. Yield: 0.44 g, 84%; MS (ESI) m/z 521.16 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 9.35 (m, 1H), 8.74 (s, 1H), 8.53 (s, 1H), 8.17(s, 1H), 7.19-7.16 (m, 4H), 6.87-6.80 (m, 4H), 6.53 (s, 2H), 6.17 (s,1H), 5.07 (s, 2H), 4.34 (s, 2H), 3.73 (s, 6H).

Synthesis of5-((6-aminopyrimidin-4-yl)amino)-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide(Cpd. No. 214)

To a solution of5-((6-aminopyrimidin-4-yl)amino)-3-chloro-N,1-bis(4-methoxybenzyl)-6-oxo-1,6-dihydropyridine-2-carboxamide(6, 0.40 g, 0.77 mmol) in dichloromethane (10 mL) was addedtrifluoroacetic acid (20 mL) and trifluoromethanesulfonic acid (1 mL) at0° C. The reaction mixture was stirred at 70° C. for 2 h. Aftercompletion, the reaction mixture was concentrated and basified by aq.ammonia at 0° C. The precipitate obtained was collected by filtration,washed with water and dried to obtain the crude. The crude was stirredwith methanol, filtered, washed with pentane and dried to afford5-((6-aminopyrimidin-4-yl)amino)-3-chloro-6-oxo-1,6-dihydropyridine-2-carboxamide(Cpd. No. 214) as yellow solid. Yield: 0.035 g, 16%; MS (ESI) m/z 281.05[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.66 (s, 1H), 8.50(s, 1H), 8.17 (s, 1H), 7.92 (s, 1H), 7.86 (s, 1H), 6.53 (s, 2H), 6.18(s, 1H).

Example 215 Synthesis of3′-(pyrimidin-4-ylamino)-4′H-spiro[cyclohexane-1,6′-imidazo[1,5-a]pyrimidine]-4′,8′(7H)-dione(Cpd. No. 215)

Synthesis of ethyl 5-bromopyrimidine-2-carboxylate (2)

To a solution of 5-bromopyrimidine-2-carboxylic acid (1, 4.0 g, 19.8mmol) in ethanol (70 mL) at room temperature was added sulfuric acid(0.5 mL). The reaction mixture was heated at 80° C. for 16 h. TLC showedconsumption of starting material. Concentrated the reaction mixtureunder reduce pressure to give residue which was diluted with water (30mL) and extracted with ethyl acetate (2×100 mL). Combined organic layerwas washed with sodium bicarbonate solution (50 mL) and then washed withbrine (50 mL), dried over anhydrous sodium sulfate, filtered andconcentrate under reduced pressure to afford ethyl5-bromopyrimidine-2-carboxylate (2) as off white solid. Yield: 3.5 g,77%; MS (ESI) m/z 230.91 [M+1]⁺.

Synthesis of 5-bromo-2-(ethoxycarbonyl)pyrimidine 1-oxide (3)

To a 0° C. cooled solution of 1-ethyl 5-bromopyrimidine-2-carboxylate(2, 1.5 g, 6.5 mmol) in dichloromethane (30 mL), trifluoroaceticanhydride (13.69 g, 65 mmol) and Urea hydrogen peroxide (6.1 g, 65 mmol)were added. The reaction mixture was stirred at room temperature for 16h. TLC showed consumption of starting material, the reaction mixture wasdiluted with water (10 mL) and neutralized with solid sodiumbicarbonate. The solution was extracted with dichloromethane (2×40 mL).The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford 5-bromo-2-(ethoxycarbonyl)pyrimidine 1-oxide (3) as yellow liquid which was used without furtherpurification. Yield: 0.64 g, crude; MS (ESI) m/z 247.13 [M+1]⁺.

Synthesis of ethyl 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate (4)

To a 0° C. cooled solution of 5-bromo-2-(ethoxycarbonyl)pyrimidine1-oxide (3, 0.62 g, 2.5 mmol) in dimethylformamide (6 mL),trifluoroacetic anhydride (3.1 g, 15 mmol) was added dropwise. Thereaction mixture was heated at 50° C. for 18 h. TLC showed consumptionof starting material and solvent was removed under reduced pressure. Theresidue was triturated with methanol (2 mL) and filtered. The solid waswashed with diethyl ether and dried under reduced pressure to affordethyl 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate (4) as off whitesolid. Yield: 0.21 g, 34%; MS (ESI) m/z 245.09 [M−1]⁻.

Synthesis of 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxamide (5)

To a solution of ethyl 5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxylate(4, 0.2 g, 0.81 mmol) in ethanol (4 mL), liquid ammonia (4 mL) was addeddropwise at room temperature. The reaction mixture was heated at 50° C.for 16 h. TLC showed consumption of starting material. Solvent wasremoved under reduced pressure and the residue was treated with methanol(1 mL) and filtered. The solid was washed with diethyl ether and driedunder reduced pressure to afford5-bromo-6-oxo-1,6-dihydropyrimidine-2-carboxamide (5) as off whitesolid. Yield: 0.14 g, 76%; MS (ESI) m/z 218.87 [M+1]⁺.

Synthesis of3′-bromo-4′H-spiro[cyclohexane-1,6′-imidazo[1,5-a]pyrimidine]-4′,8′(7′H)-dione(7)

The synthesis of intermediate 7 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 0.085 g,50%; ¹H NMR (400 MHz, DMSO-d₆) δ 10.96 (s, 1H), 8.55 (s, 1H), 6.94-7.20(m, 2H), 3.36 (s, 1H), 2.65-2.71 (m, 2H), 1.61-1.73 (m, 2H), 1.19-1.22(m, 1H).

Synthesis of3′-(pyrimidin-4-ylamino)-4′H-spiro[cyclohexane-1,6′-imidazo[1,5-a]pyrimidine]-4′,8′(7′H)-dione(Cpd. No. 215)

The synthesis of compound 215 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.014 g, 17%;MS (ESI) m/z 313.14 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.77 (s, 1H),9.42 (s, 1H), 9.34 (s, 1H), 8.77 (s, 1H), 8.38 (s, 1H), 7.35 (s, 1H),2.85-2.72 (m, 2H), 1.85-1.54 (m, 7H), 1.30-1.20 (m, 1H).

Example 216 Synthesis of8′-methyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazine]-1′,5′-dione(Cpd. No. 216)

Synthesis of methyl5-bromo-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2)

Methyl 3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2.0 g, 11.89mmol) was dissolved in dichloromethane (30 mL) and N-bromosuccinimide(2.12 g, 11.89 mmol) was added. The reaction was allowed to stir at roomtemperature for 16 h. On completion, the reaction mixture was washedwith water and brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The solid was washed with ether to afford methyl5-bromo-3-methyl-6-oxo-1,6-dihydropyrazine-2-carboxylate (2) as lightbrown solid. Yield: 1.25 g, 42%; MS (ESI) m/z 247.04 [M+1]⁺; ¹H NMR (400MHz, DMSO-d₆) δ 12.92 (brs, 1H), 3.87 (s, 4H), 2.50 (s, 3H).

Synthesis of methyl3-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyrazine-2-carboxylate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 500 mg, 48%;MS (ESI) m/z 262.22 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 12.16 (brs, 1H),9.14 (s, 1H), 8.69-8.68 (d, J=5.6 Hz, 1H), 8.49-8.47 (d, J=5.6 Hz, 1H),3.80 (s, 3H), 2.50 (s, 3H).

Synthesis of3-methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyrazine-2-carboxamide(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure K. Brown solid. Yield: 350 mg, 74%; MS(ESI) m/z 247.01 [M+1]⁺.

Synthesis of8′-methyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazine]-1′,5′-dione(Cpd. No. 216)

To a solution of3-Methyl-6-oxo-5-(pyrimidin-4-ylamino)-1,6-dihydropyrazine-2-carboxamide(5, 100 mg, 0.41 mmol) and cyclohexanone (199 mg, 2.03 mmol) inacetonitrile in a 20 mL microwave vial was added iron(III) chloride (197mg, 1.21 mmol). The reaction was heated at 80° C. for 16 h. Oncompletion of the reaction, solvent was removed under vacuum and thecrude was purified by silica gel (200-400 mesh) column chromatographyeluting with 5% methanol in dichloromethane. Appropriate columnfractions were concentrated under reduced pressure to afford8′-methyl-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyrazine]-1′,5′-dione(Cpd. No. 216) as off white solid. Yield: 8.5 mg, 6%; MS (ESI) m/z327.13 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 9.11 (s, 1H),8.88 (s, 1H), 8.72 (d, J=4.0 Hz 1H), 8.47 (d, J=4.0 Hz, 1H), 2.85-2.74(m, 2H), 2.54 (s, 3H), 1.80-1.50 (m, 7H), 1.30-120 (m, 1H).

Example 217 Synthesis of8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(Cpd. No. 217)

Synthesis of N-benzyl-3-((tert-butyldimethylsilyl) oxy) propan-1-amine(2)

To a stirred solution of 3-(benzylamino)propan-1-ol (1, 2.0 g, 12.1mmol) in dichloromethane (20 mL), imidazole (2.47 g, 36.0 mmol) andtert-butyldimethylsilyl chloride (1.1 g, 13 mmol) were added at roomtemperature. The reaction mass was stirred at room temperature for 16 h.Water was added to the reaction mixture and layers were separated. Theorganic layer was dried over sodium sulfate, filtered and concentratedto afford N-benzyl-3-((tert-butyldimethylsilyl) oxy) propan-1-amine (2)as brown solid. Yield: 3.2 g, 94%; MS (ESI) m/z 280.29 [M−1]⁻.

Synthesis of N-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl) oxy)propyl)-3-methyl-6-oxo-1, 6-dihydropyridine-2-carboxamide (4)

To a stirred solution ofN-benzyl-3-((tert-butyldimethylsilyl)oxy)propan-1-amine (2, 3.0 g, 12.9mmol) in dimethylformamide (50 mL),5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (3, 3.6 g,12.9 mmol), HBTU (6.4 g, 16.9 mmol) and N,N-diisopropylethylamine (2.2g, 16.9 mmol) were added at room temperature. The mixture was stirredfor 16 h. TLC showed completion of reaction. The reaction mixture wasquenched with aqueous sodium bicarbonate solution and extracted withethyl acetate (250 mL). The organic layer was dried over sodium sulfate,filtered and concentrated to affordN-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl) oxy)propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (4) as yellowliquid. Yield: 3.0 g, 47%; MS (ESI) m/z 495.24 [M−1]⁻.

Synthesis ofN-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide(5)

To a stirred solution ofN-benzyl-5-bromo-N-(3-((tert-butyldimethylsilyl)oxy)propyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide(4, 3.0 g, 6.0 mmol) in dioxane (20 mL), hydrochloric acid in dioxane(20 mL) was added at room temperature. The mixture was stirred for 16 h.After completion, the solvent was removed. The residue was diluted withaqueous sodium bicarbonate and extracted with 5%methanol/dichloromethane (3×200 mL). The organic layer was dried oversodium sulfate, filtered and concentrated to getN-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (5) as brown liquid. Yield: 2.2 g, 95%;MS (ESI) m/z 381.22 [M−1]⁻.

Synthesis of 2-benzyl-8-bromo-10-methyl-2, 3, 4, 5-tetrahydropyrido [1,2-a][1, 4]diazepine-1, 7-dione (6)

To a stirred solution ofN-benzyl-5-bromo-N-(3-hydroxypropyl)-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide(5, 1.5 g, 3.9 mmol) in tetrahydrofuran (30 mL), triphenylphosphine (1.5g, 5.9 mmol) and diisopropyl azodicarboxylate (1.2 g, 5.9 mmol) wereadded at 0° C. The mixture was stirred at room temperature for 16 h.After completion, solvent was removed under reduced pressure and thecrude was purified by flash chromatography eluting with 40% ethylacetate in hexane. Appropriate fractions were concentrated under reducedpressure to afford2-benzyl-8-bromo-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(6) as yellow solid. Yield: 0.9 g, 64%; MS (ESI) m/z 361.18 [M+1]⁺.

Synthesis of8-((6-(di-(tert-butoxycarbonyl)-amino)pyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(8)

The synthesis of intermediate 8 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.9 g, 69%; MS(ESI) m/z 591.66 [M+1]⁺.

Synthesis of8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(9)

The synthesis of intermediate 9 was carried out as described above usingthe general protocol of Procedure D. Yellow solid. Yield: 0.59 g, 99%;MS (ESI) m/z 391.32 [M+1]⁺.

Synthesis of8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione (Cpd. No. 217)

A vial was charged with8-((6-aminopyrimidin-4-yl)amino)-2-benzyl-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(9, 0.3 g, 76.9 mmol) and triflic acid (7.0 mL) was added. The reactionmixture was heated under microwave at 150° C. for 20 min. TLC showedcompletion of the reaction and the mixture was cooled to ambienttemperature. This was then basified with aqueous sodium bicarbonatesolution and extracted with 5% methanol/dichloromethane (3×200 mL). Theorganic layer was dried over sodium sulfate and solvent was removedunder reduced pressure to afford8-((6-aminopyrimidin-4-yl)amino)-10-methyl-2,3,4,5-tetrahydropyrido[1,2-a][1,4]diazepine-1,7-dione(Cpd. No. 217) as a brown solid. Yield: 0.06 g, 26%; MS (ESI) m/z 301.15[M+1]⁺; 1H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.36-8.20 (m, 2H),8.15 (s, 1H), 6.52 (brs, 2H), 6.13 (s, 1H), 5.05 (brs, 1H), 3.26-3.04(m, 2H), 2.95-2.80 (m, 1H), 2.13 (s, 3H), 1.87 (brs, 2H).

Example 218 Synthesis6-amino-4-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidine1-oxide (Cpd. No. 218)

Synthesis of6-amino-4-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidine1-oxide (Cpd. No. 218)

To a solution of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 0.1 g, 0.29 mmol) in dichloromethane (25 mL), 3-chloroperbenzoicacid (0.10 g, 0.59 mmol) was added. The reaction mixture was stirred atroom temperature for 16 h. After completion the reaction mixture wasdiluted with saturated sodium bicarbonate solution (50 mL) and stirredfor 30 m at room temperature. Yellow solid precipitated out and wasfiltered and dried to obtain the crude. The crude was purified by preppurification to afford6-amino-4-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidine1-oxide (Cpd. No. 218) as yellow solid. Yield: 50 mg, 50%; MS (ESI) m/z357.18 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 9.01 (s, 1H),8.53 (s, 1H), 8.23 (s, 1H), 7.48 (brs, 1H), 6.65 (s, 1H), 3.02-2.96 (m,2H), 2.42 (s, 3H), 1.75-1.58 (m, 5H), 1.45-1.42 (m, 2H), 1.22-1.19 (m,1H).

Example 219 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (Cpd. No. 219)

Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)carbamate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 320 mg,38%; MS (ESI) m/z 556.67 [M+1]⁺.

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (Cpd. No. 219)

The synthesis of compound 219 was carried out as described above usingthe general protocol of Procedure F. Light yellow solid. Yield: 274 mg,97%; MS (ESI) m/z 356.18 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.64 (brs,1H), 10.45 (s, 1H), 9.73 (s, 1H), 8.46 (s, 1H), 8.15 (s, 1H), 7.91 (brs,2H), 6.45 (s, 1H), 3.62-3.42 (m, 6H), 2.82 (s, 3H), 2.46 (s, 3H),1.81-1.78 (m, 2H).

Example 220 Synthesis of6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 220)

Synthesis ofN-(6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)-5-methylpyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid. Yield: 450 mg, 67%;MS (ESI) m/z 438.36 [M+1]⁺.

Synthesis of6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 220)

The synthesis of compound 220 was carried out as described above usingthe general protocol of Procedure I. Off white solid. Yield: 150 mg,39%; MS (ESI) m/z 370.20 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s,1H), 8.47 (s, 1H), 8.11 (s, 1H), 8.00 (s, 1H), 6.48 (s, 2H), 3.30-3.20(m, 2H), 2.78-2.75 (m, 2H), 2.44 (s, 3H), 2.40-2.32 (m, 2H), 2.24 (s,3H), 1.98 (s, 3H), 1.40-1.36 (m, 2H).

Example 221 Synthesis of6′-((2-chloropyrimidin-4-yl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 221)

Synthesis of6′-((4-methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

6′-Bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 2.0 g, 6.42 mmol) was dissolved in 2-propanol (20 mL). To thismixture was added cesium carbonate (6.28 g, 19.28 mmol), followed by(4-methoxyphenyl)methanethiol (1.18 g, 7.71 mmol). The reaction mixturewas stirred at 70° C. for 16 h. After completion, solvent was evaporatedunder reduced pressure and the crude was washed with water (50 mL)followed by diethyl ether and then dried under reduced pressure toafford6′-((4-methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3) as grey solid. Yield: 2.15 g, 87%; MS (ESI) m/z 385.5 [M+1]⁺.

Synthesis of6′-mercapto-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4)

6′-((4-Methoxybenzyl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3, 3.3 g, 8.59 mmol) was dissolved in chloroform (20 mL) andmethanesulfonic acid (10 mL) was added. The reaction mixture was stirredat 50° C. for 16 h. After completion, solvent was evaporated underreduced pressure. Obtained crude was washed with water (50 mL) followedby ethyl acetate and then dried under reduced pressure to afford6′-mercapto-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dioneas grey solid. Yield: 1.3 g, 59%; MS (ESI) m/z 265.6 [M+1]⁺.

Synthesis of6′-((2-chloropyrimidin-4-yl)thio)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 221)

The synthesis of compound 221 was carried out as described above usingthe general protocol of Procedure B. White solid; Yield: 0.4 g, 56%; MS(ESI) m/z 377.27 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (s, 1H), 8.45(d, J=5.2 Hz, 1H), 8.08 (s, 1H), 7.32 (d, J=5.6 Hz, 1H), 2.92-2.84 (m,2H), 2.42 (s, 3H), 1.74-1.71 (m, 2H), 1.65-1.52 (m, 3H), 1.47-1.44 (m,2H), 1.18-1.15 (m, 1H).

Example 222 Synthesis of6′-((6-amino-5-methylpyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 222)

Synthesis ofN-(5-methyl-6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid; Yield: 0.17 g, 31%;MS (ESI) m/z 423.21 [M+1]⁺.

Synthesis of6′-((6-amino-5-methylpyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 222)

The synthesis of compound 222 was carried out as described above usingthe general protocol of Procedure I. White solid; Yield: 0.10 g, 70%; MS(ESI) m/z 355.18 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.05 (s, 1H), 8.48(s, 1H), 8.12 (s, 1H), 8.01 (s, 1H), 6.48 (s, 2H), 2.98 (t, J=9.2 Hz,2H), 2.45 (s, 3H), 1.98 (s, 3H), 1.73-1.58 (m, 5H), 1.48-1.42 (m, 2H),1.30-1.23 (m, 1H).

Example 223 Synthesis of6′-((6-amino-5-chloropyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 223)

Synthesis of tert-butylN-tert-butoxycarbonyl-N-(5-Chloro-6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazopyridin]-6′-yl)amino)pyrimidin-4-yl)carbamate (3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Off white solid; Yield: 0.32 g,39%; MS (ESI) m/z 575.23 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s,1H), 9.03 (s, 1H), 8.79 (s, 1H), 8.55 (s, 1H), 2.96 (m, 2H), 2.5 (s,3H), 1.76-1.58 (m, 5H), 1.49 (m, 2H), 1.39 (s, 18H), 1.25 (m, 1H).

Synthesis of6′-((6-amino-5-chloropyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. No. 223)

The synthesis of compound 223 was carried out as described above usingthe general protocol of Procedure F. Yellow solid. Yield: 0.20 g, 88%;MS (ESI) m/z 375.13 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.15 (s, 1H),8.60 (s, 1H), 8.47 (s, 1H), 8.21 (s, 1H), 7.23 (brs, 2H), 2.97 (t,J=9.6, Hz, 2H), 2.46 (s, 3H), 1.76-1.58 (m, 5H), 1.48-1.42 (m, 2H),1.30-1.21 (m, 1H).

Example 224 Synthesis of6′-((2-chloropyrimidin-4-yl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 224)

Synthesis of6′-((4-methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3)

To a solution of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(1, 2.5 g, 8.03 mmol) in dimethylformamide (20 mL), sodium hydride (1.15g, 48.23 mmol) was added portion wise. The reaction mixture was stirredat 0° C. for 30 m. To the reaction mixture was added(4-methoxyphenyl)methanol (3.34 g, 24.11 mmol) and the reaction wasstirred at 80° C. for 16 h. After completion, solvent was evaporatedunder reduced pressure. Obtained crude was washed with water (50 mL)followed by diethyl ether and dried under reduced pressure to afford6′-((4-methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3) as yellow solid. Yield: 1.4 g, 48%; MS (ESI) m/z 369.15 [M+1]⁺.

Synthesis of6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4)

6′-((4-Methoxybenzyl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(3, 3.3 g, 8.59 mmol) was dissolved in 1,2-dichloroethane (25 mL) andtrifluoroacetic acid (10 mL) was added. The reaction mixture was stirredat 50° C. for 2 h. After completion, solvent was evaporated underreduced pressure. Obtained crude was washed with water (50 mL) followedby n-pentane and dried under reduced pressure to afford6′-hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4) as yellow solid. Yield: 0.85 g, 90%; MS (ESI) m/z 249.07 [M+1]⁺.

Synthesis of6′-((2-chloropyrimidin-4-yl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 224)

6′-Hydroxy-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(4, 0.5 g, 2.01 mmol) was dissolved in 2-propanol (20 mL) andN,N-diisopropylethylamine (780 mg, 6.05 mmol) and 2,4-dichloropyrimidine(0.30 g, 2.83 mmol) were added. The reaction mixture was stirred at 120°C. for 36 h. After completion, the solvent was evaporated under reducedpressure and water (100 mL) was added. The precipitated yellow solid wasfiltered and dried under reduced pressure. This crude was purified bysilica gel (220-400 mesh) column chromatography using 2-5% methanol indichloromethane as an eluent to afford6′-((2-chloropyrimidin-4-yl)oxy)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 224). Yield: 0.33 g, 46%; MS (ESI) m/z 361.12 [M+1]⁺; ¹H NMR(400 MHz, DMSO-d₆) δ 10.37 (s, 1H), 8.65 (d, J=5.6 Hz, 1H), 7.61 (s,1H), 7.28 (d, J=5.6 Hz, 1H), 6.55 (s, 2H), 2.88-2.72 (m, 2H), 2.44 (s,3H), 1.72-1.70 (m, 2H), 1.64-1.58 (m, 3H), 1.45-1.42 (m, 2H), 1.17-1.13(m, 1H).

Example 225 Synthesis of2-(6-((6-aminopyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 225)

Synthesis of di-tert-butyl(6-((1′-(cyanomethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)-12-azanecarboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Yellow solid; Yield: 0.25 g, 60%;MS (ESI) m/z 581.49 [M+1]⁺.

Synthesis of2-(6-((6-aminopyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 225)

The synthesis of compound 225 was carried out as described above usingthe general protocol of Procedure F. White solid; Yield: 37 mg, 38%; MS(ESI) m/z 381.19 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 9.47(s, 1H), 8.38 (s, 1H), 8.18 (s, 1H), 7.54 (brs, 2H), 6.34 (s, 1H), 3.74(s, 2H), 3.30-3.23 (m, 2H), 2.89-2.87 (m, 2H), 2.66-2.64 (s, 2H), 2.42(s, 3H), 1.50-1.47 (m, 2H).

Example 226 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-1′-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 226)

Synthesis of6-bromo-1′-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3)

To a solution of6-bromo-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (1, 300 mg, 0.96 mmol) in acetonitrile was added2-bromo-1,1-difluoroethane (348 mg, 2.40 mmol) and potassium carbonate(397 mg, 2.88 mmol). The reaction was heated at 90° C. for 18 h. Oncompletion of reaction, solvent was removed and the crude was purifiedby silica gel (200-400 mesh) column chromatography eluting with 5-7%methanol in dichloromethane. Appropriate column fractions wereconcentrated under reduced pressure to afford6-bromo-1′-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-c]pyridine-3,4′-piperidine]-1,5-dione(3) as light yellow solid. Yield: 180 mg, 37%; MS (ESI) m/z 378.22[M+1]⁺.

Synthesis of tert-butylN-tert-butoxycarbonyl-N-(6-((1′-(2,2-difluoroethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 200 mg,69%; MS (ESI) m/z 606.18.

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-1′-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 226)

The synthesis of compound 226 was carried out as described above usingthe general protocol of Procedure F. White solid; Yield: 14 mg, 8%; MS(ESI) m/z 406.20 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.57(s, 1H), 8.38 (s, 1H), 8.16 (s, 1H), 6.51 (s, 2H), 6.30-6.00 (m, 2H),3.25-3.22 (m, 2H), 2.94-2.91 (m, 2H), 2.87-2.79 (m, 2H), 2.69-2.63 (m,2H), 2.42 (s, 3H), 1.39-1.36 (m, 2H).

Example 227 Synthesis of6-((5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 227)

Synthesis of6-bromo-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3)

To a stirred solution of5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1, 3 g, 12.98mmol) in 1,4-dioxane (25 mL), 1-methylpiperidin-4-one (2.2 g, 19.47mmol) was added at room temperature. To the mixture 4 M hydrogenchloridein dioxane (6.5 mL, 2.59 mmol) was added dropwise. The reaction washeated up to 110° C. for 16 h. After completion, solvent was removedunder reduced pressure and obtained solid was washed with warm waterfollowed by pentane and ether to afford6-bromo-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3) as off white solid. Yield: 2.5 g, 59%; MS (ESI) m/z 326 [M+1]⁺.

Synthesis of6-((5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 227)

The synthesis of compound 227 was carried out as described above usingthe general protocol of Procedure B. Off white solid; Yield: 103 mg,18%; MS (ESI) m/z 371.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.16 (brs,1H), 8.62 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 4.00 (s,3H), 3.25-3.21 (m, 2H), 2.84-2.81 (m, 2H), 2.45 (s, 3H), 2.48-2.42 (m,2H), 2.28 (s, 3H), 1.44-1.41 (m, 2H).

Example 228 Synthesis of6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 228)

SynthesisN-(6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)-5-methoxypyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 103 mg,31%; MS (ESI) m/z 454.15 [M+1]⁺.

Synthesis of6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 228)

A flask containing tetrahydrofuran, ethanol and water (1:1:1, 5 mL each)was charged with6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-c]pyridine-3,4′-piperidine]-1,5-dione(3, 0.2 g, 0.441 mmol) and sodium hydroxide (88 mg, 2.2 mmol). Thereaction was stirred at 60° C. for 16 h. After completion, the reactionmass was extracted with 10% 2-propanol in chloroform (5×50 mL). Combinedorganic layer was concentrated and obtained solid was washed withmethanol and dried under vacuum to afford6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-c]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 228) as light yellow solid. Yield: 88 mg, 52%; MS (ESI) m/z386.19 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.11 (s, 1H), 8.45 (s, 1H),8.32 (s, 1H), 8.00 (s, 2H), 6.67 (s, 2H), 3.69 (s, 3H), 3.30-3.20 (m,2H), 2.90 (brs, 2H), 2.50-2.46 (m, 2H), 2.45 (s, 3H), 2.33 (s, 3H),1.47-1.45 (m, 2H).

Example 229 Synthesis of2-(6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 229)

Synthesis of2-(6-bromo-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(3)

A flask was charged with6-bromo-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(1, 0.50 g, 1.6 mmol) and acetonitrile (15 mL). The reaction mass wascooled to 0° C. and potassium carbonate (664 mg, 4.8 mmol) was addedfollowed by the addition of 2-bromoacetonitrile (288.18 mg, 2.40 mmol).The reaction mass was stirred at 70° C. for 16 h. After completion,reaction mixture was diluted with saturated ammonium chloride solution(50 mL). The precipitate was filtered and dried under reduced pressureto afford2-(6-bromo-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(3) as white solid. Yield: 0.32 g, 58%; MS (ESI) m/z 351.26 [M+1]⁺.

Synthesis of2-(6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 229)

The synthesis of compound 229 was carried out as described above usingthe general protocol of Procedure B. Yellow solid. Yield: 0.068 g, 20%;MS (ESI) m/z 396.5 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆ with d₁-TFA) δ 8.94(s, 1H), 8.53 (s, 1H), 8.44 (s, 1H), 4.47 (s, 2H), 4.07 (s, 3H),3.71-3.68 (m, 2H), 3.47-3.39 (m, 4H), 2.47 (s, 3H), 1.92-1.89 (m, 2H).

Example 230 Synthesis of1′-(2,2-difluoroethyl)-6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 230)

Synthesis of1′-(2,2-difluoroethyl)-6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 230)

The synthesis of compound 230 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 65 mg, 45%;MS (ESI) m/z 421.13 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.22 (s, 1H),8.64 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.24 (s, 2H), 6.30-6.00 (m,1H), 4.00 (s, 1H), 3.31-3.17 (m, 2H), 2.95-2.92 (m, 2H), 2.87-2.78 (m,2H), 2.68-2.62 (m, 2H), 2.49 (s, 3H), 1.43-1.40 (m, 2H).

Example 231 Synthesis of6′-((6-amino-5-methoxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 231)

Synthesis ofN-(5-methoxy-6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 0.3 g,71%; MS (ESI) m/z 439.14 [M+1]⁺.

Synthesis of6′-((6-amino-5-methoxypyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(Cpd. No. 231)

The synthesis of compound 231 was carried out as described above usingthe general protocol of Procedure I. Yellow solid; Yield: 0.085 g, 27%;MS (ESI) m/z 371.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.06 (s, 1H),8.47 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 6.67 (s, 2H), 3.69 (s, 3H),3.02-2.95 (m, 2H), 2.45 (s, 3H), 1.78-1.58 (m, 5H), 1.47-1.43 (m, 2H),1.29-1.20 (m, 1H).

Example 232 Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 232)

Synthesis of N-(6-((8-methyl-1,5-dioxo-1′-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Yellow solid. Yield: 300 mg, 60%;MS (ESI) m/z 492.10 [M+1]⁺.

Synthesis of6-((6-aminopyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 232)

The synthesis of compound 232 was carried out as described above usingthe general protocol of Procedure I. White solid; Yield: 60 mg, 23%; MS(ESI) m/z 424.19 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1H), 8.65(s, 1H), 8.37 (s, 1H), 8.18 (s, 1H), 6.60 (s, 2H), 6.18 (s, 1H),3.27-3.22 (m, 4H), 2.95-2.90 (m, 2H), 2.85-2.76 (m, 2H), 2.42 (s, 3H),1.41-1.36 (m, 2H).

Example 233 Synthesis of6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 233)

Synthesis ofN-(6-((1′-(2,2-difluoroethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)-5-methylpyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 0.35 g,65%; MS (ESI) m/z 488.27 [M+1]⁺.

Synthesis of6-((6-amino-5-methylpyrimidin-4-yl)amino)-1′-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 233)

The synthesis of compound 233 was carried out as described above usingthe general protocol of Procedure I. Off white solid; Yield: 80 mg, 26%;MS (ESI) m/z 420.20 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.13 (s, 1H),8.48 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 6.48 (s, 2H), 6.30-6.00 (m,1H), 3.27-3.21 (m, 2H), 2.94-2.91 (m, 2H), 2.86-2.77 (m, 2H), 2.67-2.61(m, 2H), 2.44 (s, 3H), 1.98 (s, 3H), 1.41-1.38 (m, 2H).

Example 234 Synthesis of6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 234)

SynthesisN-(5-methoxy-6-((8-methyl-1,5-dioxo-1′-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 400 mg,76%; MS (ESI) m/z 522.19 [M+1]⁺.

Synthesis of6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 234)

The synthesis of compound 234 was carried out as described above usingthe general protocol of Procedure I. Light yellow solid; Yield: 100 mg,29%; MS (ESI) m/z 354.12 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.19 (s,1H), 8.45 (s, 1H), 8.32 (s, 1H), 8.00 (s, 1H), 6.67 (s, 2H), 3.69 (s,3H), 3.27-3.21 (m, 4H), 2.97-2.90 (m, 2H), 2.83-2.77 (m, 2H), 2.45 (s,3H), 1.42-1.38 (m, 2H).

Example 235 Synthesis of6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 235)

Synthesis of6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 235)

The synthesis of compound 235 was carried out as described above usingthe general protocol of Procedure B. Off white solid; Yield: 0.13 g,39%; MS (ESI) m/z 439.21 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s,1H), 8.65 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 8.24 (s, 1H), 4.00 (s,3H), 3.32-3.22 (m, 4H), 2.96-2.90 (m, 2H), 2.85-2.79 (m, 2H), 2.45 (s,3H), 1.42-1.39 (m, 2H).

Example 236 Synthesis of6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 236)

Synthesis of6-bromo-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Yield: 5.0 g, 58%; MS (ESI) m/z394.08 [M+1]⁺.

Synthesis of N-(5-methyl-6-((8-methyl-1,5-dioxo-1′-(2, 2,2-trifluoroethyl)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Brown solid; Yield: 0.32 g, 62%; MS(ESI) m/z 506.23 [M+1]⁺.

Synthesis of 6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 236)

The synthesis of compound 236 was carried out as described above usingthe general protocol of Procedure I. Yield: 70 mg, 27%; MS (ESI) m/z438.16 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆ with d₁-TFA) δ 10.17 (s, 1H),8.48 (s, 1H), 8.12 (s, 1H), 8.00 (s, 1H), 6.48 (s, 2H), 3.32-3.20 (m,4H), 2.95-2.93 (m, 2H), 2.85-2.75 (m, 2H), 2.45 (s, 3H), 1.98 (s, 3H),1.41-1.38 (m, 2H).

Example 237 Synthesis of6-((6-amino-5-chloropyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 237)

Synthesis ofN-(5-chloro-6-((1′,8-dimethyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Light brown solid; Yield: 210 mg,50%; MS (ESI) m/z 458.12 [M+1]⁺.

Synthesis of6-((6-amino-5-chloropyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 237)

A flask containing tetrahydrofuran, ethanol and water (1:1:1, 5 mL each)was charged with6-((6-amino-5-methoxypyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-c]pyridine-3,4′-piperidine]-1,5-dione(3, 0.17 g, 0.371 mmol) and sodium hydroxide (75 mg, 1.85 mmol). Thereaction was stirred at 50° C. for 16 h. After completion, the reactionmass was extracted with 10% methanol in dichloromethane. Combinedorganic layer was washed with water, brine, dried over anhydrous sodiumsulfate concentrated under vacuum obtained solid was washed with etherand dried under vacuum to afford6-((6-amino-5-chloropyrimidin-4-yl)amino)-1′,8-dimethyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dioneas light yellow solid. Yield: 88 mg, 31%; MS (ESI) m/z 390.14 [M+1]⁺; ¹HNMR (400 MHz, DMSO-d₆) δ 10.16 (s, 1H), 8.52 (s, 1H), 8.50 (s, 1H), 8.17(s, 1H), 7.10 (brs, 2H), 3.30-3.20 (m, 2H), 2.90-2.82 (brs, 2H),2.49-2.40 (m, 2H), 2.46 (s, 3H), 2.30 (s, 3H), 1.46-1.40 (m, 2H).

Example 238 Synthesis of2-(6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 238)

Synthesis of tert-butyl6-((5-chloro-6-(cyclopropanecarboxamido)pyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.35 g,crude; MS (ESI) m/z 544.27 [M+1]⁺.

Synthesis of tert-butyl6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure I. Yellow solid; Yield: 300 mg, crude;MS (ESI) m/z 476.23 [M+1]⁺.

Synthesis of6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure F. Light yellow solid; Yield: 0.075 g,crude; MS (ESI) m/z 376.23 [M+1]⁺.

Synthesis of2-(6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 238)

6-((6-Amino-5-chloropyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-c]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (5, 75 mg, 0.20 mmol) was dissolved in dimethylformamide(5 mL). To this mixture N,N-diisopropylethylamine (77 mg, 0.60 mmol) andbromoacetonitrile (36 mg, 0.30 mmol) were added. The reaction mixturewas stirred at room temperature for 2 h. After completion reactionmixture was diluted with saturated ammonium chloride solution (50 mL).The yellow precipitate out was filtered and dried under reducedpressure. The crude was purified by prep purification to afford2-(6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 238) as white solid. Yield: 14 mg, 17%; MS (ESI) m/z 414.85[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆ with d₁-TFA) δ 8.49 (s, 1H), 8.33 (s,1H), 4.49 (s, 2H), 3.76-3.71 (m, 2H), 3.58-3.41 (m, 4H), 2.42 (s, 3H),1.90-1.87 (m, 2H).

Example 239 Synthesis of6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-2′,3′,5′,6′-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-1,5-dione(Cpd. No. 239)

Synthesis of6-bromo-8-methyl-2′,3′,5′,6′-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-1,5-dione(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure A. Off white solid; Yield: 1.4 g, 69%;MS (ESI) m/z 313 [M+1]⁺.

Synthesis of tert-butyl(8-methyl-1,5-dioxo-1,2′,3′,5,5′,6′-hexahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-6-yl)carbamate(5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 1.2 g,crude; MS (ESI) m/z 350 [M+1]⁺.

Synthesis of6-amino-8-methyl-2′,3′,5′,6′-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-1,5-dionehydrochloride (6)

The synthesis of intermediate 6 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 0.45 g,42%; MS (ESI) m/z 285 [M+1]⁺.

Synthesis of6-((6-(di-(tert-butoxycarbonyl)-amino)-5-methylpyrimidin-4-yl)amino)-8-methyl-2′,3′,5′,6′-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-1,5-dione(8)

The synthesis of intermediate 8 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.26 g,44%; MS (ESI) m/z 557 [M+1]⁺.

Synthesis of6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-2′,3′,5′,6′-tetrahydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-pyran]-1,5-dione(Cpd. No. 239)

The synthesis of compound 239 was carried out as described above usingthe general protocol of Procedure F. Off white solid; Yield: 0.12 g,72%; MS (ESI) m/z 357 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H),8.54 (s, 1H), 8.41 (s, 1H), 8.21 (s, 1H), 7.73 (brs, 2H), 3.96-3.90 (m,2H), 3.69 (t, J=12.44 Hz, 2H), 3.25-3.15 (m, 2H), 2.46 (m, 3H), 2.07 (s,3H), 1.46-1.41 (m, 2H).

Example 240 Synthesis of2-(6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 240)

Synthesis of tert-butyl6-((6-(cyclopropanecarboxamido)-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 0.75 g,83%; MS (ESI) m/z 524.41 [M+1]⁺.

Synthesis of tert-butyl6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure I. Yellow solid. Yield: 650 mg, 33%;MS (ESI) m/z 456.33 [M+1]⁺.

Synthesis of6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure F. Light brown solid; Yield: 0.41 g,80%; MS (ESI) m/z 356.12 [M+1]⁺.

Synthesis of2-(6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 240)

6-((6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (5, 0.2 g, 0.56 mmol) was dissolved in dimethylformamide(10 mL). To it was added N,N-diisopropylethylamine (0.22 g, 1.68 mmol),followed by bromoacetonitrile (0.10 g, 0.84 mmol). The reaction mixturewas stirred at room temperature for 30 min. After completion reactionmixture was diluted with 50 mL ethyl acetate, It was washed withsaturated ammonium chloride solution and brine solution, solvent wasremoved under reduced pressure and the resulting residue was furtherwashed with methanol ether and pentane, dried under vacuum to afford2-(6-(6-amino-5-methylpyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 240) as light yellow solid. Yield: 95 mg, 43%; MS (ESI) m/z395.18 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 8.48 (s, 1H),8.12 (s, 1H), 7.99 (s, 1H), 6.47 (s, 2H), 3.74 (s, 2H), 3.33-3.30 (m,2H), 2.92-2.85 (m, 2H), 2.70-2.58 (m, 2H), 2.44 (s, 3H), 1.98 (s, 3H),1.53-1.46 (m, 2H).

Example 241 Synthesis of6-((6-amino-5-chloropyrimidin-4-yl)amino)-1′-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 241)

Synthesis ofN-(5-chloro-6-((1′-(2,2-difluoroethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 0.38 g,70%; MS (ESI) m/z 508.18 [M+1]⁺.

Synthesis of6-((6-amino-5-chloropyrimidin-4-yl)amino)-1′-(2,2-difluoroethyl)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 241)

The synthesis of compound 241 was carried out as described above usingthe general protocol of Procedure I. White solid; Yield: 25 mg, 8%; MS(ESI) m/z 410.14 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s, 1H), 8.53(s, 1H), 8.51 (s, 1H), 8.18 (s, 1H), 7.21 (brs, 2H), 6.46 (t, J=56.0 Hz,1H), 3.35-2.98 (m, 8H), 2.46 (s, 3H), 1.71-1.52 (m, 2H).

Example 242 Synthesis of6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 242)

Synthesis of N-(5-chloro-6-((8-methyl-1,5-dioxo-1′-(2,2,2-trifluoroethyl)-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Off white solid; Yield: 0.40 g; MS(ESI) m/z 524.1

Synthesis of6-((6-amino-5-chloropyrimidin-4-yl)amino)-8-methyl-1′-(2,2,2-trifluoroethyl)-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 242)

The synthesis of compound 242 was carried out as described above usingthe general protocol of Procedure I. Yield: 60 mg, 17%; MS (ESI) m/z458.11 [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (brs, 1H), 8.53 (s,1H), 8.50 (s, 1H), 8.17 (s, 1H), 7.10 (brs, 2H), 3.40-3.22 (m, 4H),2.96-2.93 (m, 2H), 2.84-2.78 (m, 2H), 2.46 (s, 3H), 1.42-1.39 (m, 2H).

Example 243 Synthesis of2-(6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 243)

Synthesis of tert-butyl6-((6-(cyclopropanecarboxamido)-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure B. Light yellow solid; Yield: 0.55 g;MS (ESI) m/z 540.31 [M+1]⁺.

Synthesis of tert-butyl6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1′-carboxylate(4)

The synthesis of intermediate 4 was carried out as described above usingthe general protocol of Procedure I. Yellow solid; Yield: 250 mg; MS(ESI) m/z 472.28 [M+1]⁺.

Synthesis of6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (5)

The synthesis of intermediate 5 was carried out as described above usingthe general protocol of Procedure F. Yellow solid; Yield: 0.18 g; MS(ESI) m/z 372.22 [M+1]⁺.

Synthesis of2-(6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 243)

6-((6-Amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dionehydrochloride (5, 0.18 g, 0.44 mmol) was dissolved in dimethylformamide(5 mL). To this mixture N,N-diisopropylethylamine (0.23 g, 1.76 mmol)was added followed by bromoacetonitrile (79 mg, 0.66 mmol). The reactionmixture was stirred at room temperature for 2 h. After completion thereaction mixture was diluted with saturated ammonium chloride solution(50 mL). Yellow precipitate was filtered and dried under reducedpressure. The compound was then purified by prep purification to afford2-(6-((6-amino-5-methoxypyrimidin-4-yl)amino)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-1′-yl)acetonitrile(Cpd. No. 243) as white solid. Yield: 40 mg, 22%; MS (ESI) m/z 411.20[M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆ with d₁-TFA) δ 8.37 (s, 1H), 8.27 (s,1H), 4.49 (s, 2H), 3.76 (s, 3H), 3.74-3.71 (m, 2H), 3.56-3.40 (m, 4H),2.43 (s, 3H), 1.90-1.87 (m, 2H).

Example 244 Synthesis of1′-(2,2-difluoroethyl)-6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 244)

Synthesis ofN-(6-((1′-(2,2-difluoroethyl)-8-methyl-1,5-dioxo-1,5-dihydro-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidin]-6-yl)amino)-5-methoxypyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 was carried out as described above usingthe general protocol of Procedure H. Light yellow solid; Yield: 0.30 g,26%; MS (ESI) m/z 504.14 [M+1]⁺.

Synthesis of1′-(2,2-difluoroethyl)-6-((5-methoxypyrimidin-4-yl)amino)-8-methyl-2H-spiro[imidazo[1,5-a]pyridine-3,4′-piperidine]-1,5-dione(Cpd. No. 244)

The synthesis of compound 244 was carried out as described above usingthe general protocol of Procedure I. Light brown solid; Yield: 27 mg,10%; MS (ESI) m/z [M+1]⁺; ¹H NMR (400 MHz, DMSO-d₆ with d₁-TFA) δ 8.42(s, 1H), 8.26 (s, 1H), 6.56 (t, J=56 Hz, 1H), 384-3.64 (m, 7H),3.60-3.40 (m, 4H), 2.46 (s, 3H), 1.92-1.86 (m, 2H).

Example 245 Synthesis of3′-((6-aminopyrimidin-4-yl)amino)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione(Cpd. No. 245)

Synthesis of4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one(2)

Treat a solution of methyl 3-(bromomethyl)-4-methoxypicolinate (1.0mmol, 1 eq) in tetrahydrofuran with 4-methoxybenzylamine (2.0 mmol, 2eq) and stir the reaction for 16 h. After completion dilute the mixturewith ethyl acetate and water and separate the layers. Wash the organiclayer with 1 M hydrochloric acid and water. Concentrate the organiclayer to give crude. Purify the crude by silica gel columnchromatography to afford4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one(2).

Synthesis of4′-methoxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one(4)

To a solution of4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one(2, 1.0 mmol, 1 eq) in tetrahydrofuran (25 mL) add sodium hydride (2.5mmol, 2.5 eq) at 0° C. Stir the mixture for 20 min and then add1,5-dibromo pentane (3, 1.5 mmol, 1.5 eq) and stir for 8 h. Aftercompletion quench the mixture with water at 0° C. and add ethyl acetate.Separate the layer and remove the solvent to get crude. Purify the crudeby silica gel column chromatography to afford4′-methoxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6H)-one(4).

Synthesis of4′-hydroxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one(5)

Treat a solution of4′-methoxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6H)-one(4, 1.0 mmol, 1 eq) in dichloromethane (25 mL) with boron tribromide(2.0 mmol, 2 eq) at 0° C. Stir the mixture for 2 h at room temperatureand quench with water at 0° C. Extract the mixture with ethyl acetateand remove the solvent under reduced pressure to get the crude. Puritythe crude by silica gel column chromatography to get4′-hydroxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one(5).

Synthesis of6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione(6)

To a solution of4′-hydroxy-6′-(4-methoxybenzyl)spiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-7′(6′H)-one(1.0 mmol, 1 eq) in tetrahydrofuran (25 mL), add sodium hydride (2.5mmol, 2.5 eq) at 0° C. and stir for 20 min. Add iodomethane (2.5 mmol,2.5 eq) to the above mixture and stir for 16 h. After completion addwater to the reaction and extract with ethyl acetate. Remove the solventunder reduced pressure to get the crude which is purified by columnchromatography to give6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione(6).

Synthesis of 3′-bromo-6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′7′(1′H,6′H)-dione (7)

To a solution of6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione(1.0 mmol, 1 eq) in carbon tetrachloride (25 mL), add N-bromosuccinimideand heat the mixture at 90° C. for 16 h. After completion the mixturewas diluted with water and extracted with ethyl acetate. Remove thesolvent under reduced pressure to get the crude. Purify the crude bycolumn chromatography to afford3′-bromo-6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione (7).

Synthesis ofN-(6-((1′-methyl-4′,7′-dioxo-1′,4′,6′,7′-tetrahydrospiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridin]-3′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide (9)

The synthesis of intermediate 9 is carried out as described above usingthe general protocol of Procedure B.

Synthesis of3′-((6-aminopyrimidin-4-yl)amino)-6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione(10)

The synthesis of intermediate 10 is carried out as described above usingthe general protocol of Procedure I.

Synthesis of3′-((6-aminopyrimidin-4-yl)amino)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione(Cpd. No. 245)

Treat a solution of3′-((6-aminopyrimidin-4-yl)amino)-6′-(4-methoxybenzyl)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione(1.0 mmol, 1 eq) in 1,2-dichloroethane (15 mL) with trifluoroacetic acid(20 mmol, 20 eq) and heat the mixture to 100° C. for 5 h. Aftercompletion, cool the mixture and remove the solvent. Triturate themixture with ether to get solid. The solid is again triturated withmethanol to get3′-((6-aminopyrimidin-4-yl)amino)-1′-methylspiro[cyclohexane-1,5′-pyrrolo[3,4-b]pyridine]-4′,7′(1′H,6′H)-dione(Cpd. No. 245).

Example 246 Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-indolizine]-1′,5′-dione(Cpd. No. 246)

Synthesis of5-bromo-N-methoxy-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide(2)

To a solution of 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylicacid (1, 1.0 mmol, 1 eq) in dimethylformamide (25 mL), addN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (2 mmol, 2 eq),triethylamine (3.0 mmol, 3 eq) and N,O-dimethylhydroxylaminehydrochloride (1.5 mmol, 1.5 eq) and stir the reaction for 6 h. Aftercompletion add water to the mixture and extract with ethyl acetate. Washthe ethyl acetate layer with water and brine, remove the solvent underreduced pressure to get5-bromo-N-methoxy-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide(2).

Synthesis of 5-bromo-N-methoxy-1-(4-methoxybenzyl)-N,3-dimethyl-6-oxo-1, 6-dihydropyridine-2-carboxamide (3)

Add sodium hydride (2.5 mmol, 2.5 eq) to a cooled solution of5-bromo-N-methoxy-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide(2, 1.0 mmol, 1 eq) in dimethylformamide (25 mL) and stir the reactionfor 20 min. Add 4-methoxybenzyl chloride (1.2 mmol, 1.2 eq) and stir thereaction for 16 h. After completion, quench the reaction with water andextract with ethyl acetate. Remove the solvent and purify the crude bycolumn chromatography to afford5-bromo-N-methoxy-1-(4-methoxybenzyl)-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide(3).

Synthesis of ethyl3-(5-bromo-1-(4-methoxybenzyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2-(1-hydroxycyclohexyl)-3-oxopropanoate(5)

To a solution of ethyl 2-(1-hydroxycyclohexyl)acetate (4, 1.2 mmol, 1.2eq) in tetrahydrofuran (15 mL), add lithium diisopropylamide (2.5 mmol,2.5 eq) at −78° C. and stir the reaction for 20 min. Add a solution of5-bromo-N-methoxy-1-(4-methoxybenzyl)-N,3-dimethyl-6-oxo-1,6-dihydropyridine-2-carboxamide(3, 1.0 mmol, 1.0 eq) in tetrahydrofuran (10 mL) at −78° C. in 10 minand continue stirring for another 3 h. After completion, add saturateaqueous ammonium chloride solution and extract the reaction mass withethyl acetate. Evaporate the solvent under reduced pressure and to getthe crude which is passed through a silica gel bed to get ethyl3-(5-bromo-1-(4-methoxybenzyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2-(1-hydroxycyclohexyl)-3-oxopropanoate(5).

Synthesis of ethyl6′-bromo-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizine]-2′-carboxylate(6)

To a solution of ethyl3-(5-bromo-1-(4-methoxybenzyl)-3-methyl-6-oxo-1,6-dihydropyridin-2-yl)-2-(1-hydroxycyclohexyl)-3-oxopropanoate(5, 1.0 mmol, 1.0 eq) in 1,2-dichloroethane (15 mL), add trifluoroaceticacid (10 mmol, 10 eq) and heat the reaction at 60° C. for 16 h. Aftercompletion, remove the solvent and quench the reaction with ammonia andextract with dichloromethane. Remove the solvent under reduced pressureand purify the crude using silica gel column chromatography to affordethyl6′-bromo-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizine]-2′-carboxylate(6).

Synthesis of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-indolizine]-1′,5′-dione(7)

To a solution of ethyl6′-bromo-8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizine]-2′-carboxylate(6, 1.0 mmol, 1.0 eq) in dimethylsulfoxide (15 mL) add lithium chloride(5.0 mmol, 5 eq) and heat the reaction at 140° C. for 16 h. Aftercompletion cool the reaction, add water and extract withdichloromethane. Remove the solvent under reduced pressure and purifythe crude by silica gel column chromatography to get6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-indolizine]-1′,5′-dione(7).

Synthesis ofN-(6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(9)

The synthesis of intermediate 9 is carried out as described above usingthe general protocol of Procedure H.

Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-indolizine]-1′,5′-dione(Cpd. No. 246)

The synthesis of compound 246 is carried out as described above usingthe general protocol of Procedure I.

Example 247 Synthesis of6′-((6-amino-5-methylpyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-indolizine]-1′,5′-dione(Cpd. No. 247)

Synthesis ofN-(5-methyl-6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-indolizin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(3)

The synthesis of intermediate 3 is carried out as described above usingthe general protocol of Procedure B.

Synthesis of6′-((6-amino-5-methylpyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-indolizine]-1′,5′-dione(Cpd. No. 247)

The synthesis of compound 247 is carried out as described above usingthe general protocol of Procedure I.

Example 248 Large-Scale Synthesis of Intermediates and Formula ICompounds

Compounds in accordance with the present invention are candidatetherapeutics for treating Mnk related disorders, such as inflammatorydisorders and cancer. To provide commercial quantities of the inventivecompounds, the present invention illustrates a large-scale syntheticprotocol for an exemplary Formula I compound as well as methods for themanufacture and characterization of the hydrochloride salt form(HCl-salt form) of such a compound.

Preparation of N-(6-aminopyrimidin-4-yl) cyclopropanecarboxamide

A. Preparation of Di-tert-butyl (6-chloropyrimidin-4-yl) carbamate (2)

To a stirred solution of 6-chloropyrimidin-4-amine (4900 g, 1 equiv,37.08 moles) in tetrahydrofuran (10 V, 50 L), at 0° C. was added N,N-dimethylaminopyridine (463 g, 0.1 equiv, 3.70 moles). Di-tert-butyldicarbonate (24.8 L, 3 equiv, 113.9 moles) was then added slowly over 1h (gas evolution was observed) to the resultant reaction. The reactionmixture became dark brown with stirring at room temperature over aperiod of 16 h. Progress of the reaction was monitored by TLC and LCMS.LCMS showed the complete disappearance of SM, as well as peakscorresponding to the product, 73.89% at RT-2.55 ((M+1)-330.3);tert-butyl (6-chloropyrimidin-4-yl) carbamate side product, 4.09% atRT-1.98 ((M+1)-330.3).

After completion of reaction, the reaction mixture was poured into anice/water mixture (30 L), and further stirred for 30 min prior tosolvent extraction of the aqueous phase with ethyl acetate (10 L). Theorganic and aqueous phases were separated and the resultant aqueouslayer was extracted twice with ethyl acetate (2×10 L). The combinedorganic layer was washed twice with water (2×10 L), then brine (1×10 L),and dried over anhydrous sodium sulfate. The dry organic layer wasconcentrated under reduced pressure at 50° C. to obtain crude productwhich was slurried with hexane (10 L) for 1 h, filtered and dried underreduced pressure at 50° C. to obtain brick red solid. Yield: 10.3 Kg,(82.6%). MS (ESI) m/z 329.78 [M+1]+; LCMS purity: 99.37%; 1H NMR (400MHz, DMSO-d6) δ: 8.86 (s, 1H), 7.85 (s, 1H), 1.48 (s, 18H).

B. Preparation of di-tert-butyl (6-(cyclopropanecarboxamido)pyrimidin-4-yl) carbamate (3)

To a stirring solution of di-tert-butyl (6-chloropyrimidin-4-yl)carbamate (5000 g, 1 equiv, 15.20 moles) in dioxane (5 V, 25 L), at roomtemperature was added cyclopropanecarboxamide (1291 g, 1 equiv, 15.20moles) followed by the addition of cesium carbonate (3950 g, 0.8 equiv,12.15 moles). After purging the reaction mixture (dark brown solution)with argon for 30 minutes, xantphos (120 g, 0.015 equiv, 0.23 moles),and palladium (II) acetate (51 g, 0.015 equiv, 0.23 moles) were added.Purging of reaction mass with argon was continued for another 15 min andthe reaction mixture was then heated to 90° C. and kept at thattemperature for 4 h, during which time the color of the reaction masschanged to orange. Progress of reaction was monitored by TLC and LCMS.LCMS showed complete disappearance of SM, and a peak corresponding toproduct at RT-2.32 min., 86.92%, ((M+1)-379.15). In addition, the LCMSshowed peaks corresponding to tert-butyl (6-(cyclopropanecarboxamido)pyrimidin-4-yl) carbamate 3.83%; at RT-1.94 ((M+1)-279.08) and someunknown byproducts (5.18% at RT-2.43 (M+1)-605.2, 1.48% at RT-2.83(M+1)-589.2).

After completion of the reaction as judged by TLC and LCMS, the reactionmixture was cooled to 50° C. and was filtered through celite bed. Thecelite bed was washed with EtOAc (3×10 L) to ensure complete extractionof the product. Combined organic layers were washed with water (2×10 L),dried over anhydrous sodium sulphate and concentrated under reducedpressure to get crude (6.2 Kg). Diethyl ether (6.0 L) was added to thecrude material and the mixture was stirred for 30 min to get freeflowing solid. The solid was filtered, washed with ether (2×1 L) andthen dried to afford di-tert-butyl (6-(cyclopropanecarboxamido)pyrimidin-4-yl) carbamate as an orange solid. This compound was used inthe next step without further purification. Yield: 4.5 Kg, (78.2%); MS(ESI) m/z 378.43 [M+1]+; LCMS purity: 95.10%; 1H NMR (400 MHz, DMSO-d6)δ: 11.30 (s, 1H), 8.66 (s, 1H), 8.25 (s, 1H), 2.02 (m, 1H), 1.46 (s,18H), 0.85 (m, 4H).

C. Preparation of N-(6-aminopyrimidin-4-yl) cyclopropanecarboxamide (4)

Trifluoroacetic acid (16 L, 10 equiv, 212 moles) was slowly added over 1h to a stirring solution of di-tert-butyl (6-(cyclopropanecarboxamido)pyrimidin-4-yl) ((3); 8050 g, 1 equiv, 21.20 moles) in dichloromethane(5 V, 40 L). Evolution of gas was observed during the addition oftrifluoroacetic acid and the reaction became dark brown when stirredcontinuously for 4 h at room temperature. Progress of reaction wasmonitored by TLC.

After completion of reaction, the reaction mass was concentrated todryness under reduced pressure (TFA must be distilled off as much aspossible prior to addition of ammonia) and dichloromethane (25 L) wasadded to the residue. The mixture was cooled to 0° C. and NH4OH (25% aq.Solution, 6 L) was added slowly (pH-10) over 30 min while stirring thereaction mixture continuously. The resulting mixture was stirred at 0°C. for an additional 30 min and the solid formed was filtered and washedwith water (2×10 L) followed by washing with methanol (2×2 L) anddichloromethane (15 L). The washed solid was dried under high vacuumovernight to afford N-(6-aminopyrimidin-4-yl) cyclopropanecarboxamide ascreamish yellow solid. Yield: 2.32 Kg (61.02%); MS (ESI) m/z 178.19[M+1]+; UPLC: 99.80%; 1H NMR (400 MHz, DMSO-d6) δ: 10.54 (s, 1H), 8.10(s, 1H), 7.10 (s, 1H), 6.72 (brs, 2H), 1.97 (m, 1H), 0.79 (m, 4H).

The final material from all batches were combined, slurried withdichromethane (10 L) for 20 min, filtered and dried under vacuum for 6 hto obtain a single batch of N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (3665.3).

Preparation of ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide

A. Preparation of ethyl 5-bromo-3-methylpicolinate (2)

To a stirring solution of 5-bromo-3-methylpicolinic acid (10000 g, 1equiv, 46.29 moles) in ethanol (50 L) at 0° C. was added sulfuric acid(2.52 L, 1 equiv, 46.29 moles) over 1 h. Following addition of sulfuricacid, the mixture was heated at 95° C. for 20 h. Reaction progress wasmonitored by using TLC and LCMS. After 20 hours, LCMS showed 12.61%unreacted SM, at RT-0.67 ((M−1)-215.92) and 86.95% product at RT-2.04((M+1)-244.2). The reaction mass heated for additional 6 h and LCMSanalysis following the additional heating showed 10.07% unreacted SM, atRT-0.7 and 89.93% product at RT-2.08 ((M+1)-244.2. The reaction wasstopped by concentrating the reaction mixture under reduced pressure toremove as much solvent as possible. To the residue was addeddichloromethane (DCM), (25 L) and the reaction mixture was poured intoice cold water (20 L). The organic (DCM) layer was separated from theaqueous layer and the latter was further extracted twice with DCM (10L). The combined organic layers were washed with saturated sodiumbicarbonate solution (30 L), dried over sodium sulfate, and concentratedunder reduced pressure to obtain a brown oil. This brown oil was used inthe next step without further purification. Yield: 10.1 Kg, (89.4%); MS(ESI) m/z 244.2 [M+1]+; LCMS purity: 99.11%; 1H NMR (400 MHz, DMSO-d6)δ: 8.61 (s, 1H), 8.13 (s, 1H), 4.29 (q, 2H), 2.44 (s, 1H), 1.28 (t, 3H).

B. Preparation of 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine 1-oxide(3)

To a stirring solution of ethyl 5-bromo-3-methylpicolinate (9.49 Kg, 1equiv, 38.88 moles) in dichloromethane (47.5 L) at 0° C. was added ureahydrogen peroxide (6.3 Kg, 1.75 equiv, 68.04 moles), followed by theaddition of trifluoroacetic anhydride (9.7 L, 1.75 equiv, 68.04 moles)at 0° C. over a period of 3 h. This reaction is strongly exothermic(0-30° C.). Following addition, the reaction mixture was gently warmedto room temperature (RT) and permitted to stir at RT for 16 h. Reactionprogress was monitored by using TLC and LCMS analysis. At the end of 16hours, LCMS showed 0.74% unreacted SM at RT-2.04 ((M+1)-244.02); 91.61%product at RT-1.38 ((M+1)-260.01) and some unknown byproducts (4.67% atRT-1.28 (M+1)-188.1, 2.98% at RT-1.90 (M+1)-217.11).

The crude reaction mixture was poured into an ice/water mixture (30 L)and the organic and aqueous phases were permitted to separate. Theaqueous layer was extracted with dichloromethane (10 L), separated fromthe aqueous layer and combined with the first organic layer. Thecombined organic layers were then washed with aqueous sodium bicarbonatesolution (50 L), followed by water (20 L), dried over sodium sulfate andconcentrated to afford 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine1-oxide as a reddish yellow oil. This compound was used for the nextstep without further purification. Yield: 9 Kg, (89%); MS (ESI) m/z260.09 [M+1]+; LCMS purity: 99.34%; 1H NMR (400 MHz, DMSO-d6) δ: 8.56(s, 1H), 7.67 (s, 1H), 4.32 (q, 2H), 2.21 (s, 3H), 1.27 (t, 3H).

C. Preparation of ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (4)

To a stirring solution of 5-bromo-2-(ethoxycarbonyl)-3-methylpyridine1-oxide (9 Kg, 1 equiv, 34.62 moles) in N, N-dimethylformamide (35 L) atRT was added trifluoroacetic anhydride (8.65 L, 1.75 equiv, 60.58moles), over a period of 3 h. The temperature of the reaction wasmaintained at 35-40° C. during the addition of trifluoroaceticanhydride. The reaction mixture was stirred at 40° C. (internal) for 2 hand reaction progress was monitored by using TLC and LCMS analysis. LCMSanalysis showed 6.26% unreacted SM at RT-1.37 ((M+1)-260.01), 31.33%product at RT-1.58 ((M+1)-259.97), 25.88% DMF at RT-0.31 and someunknown byproducts (8.06% at RT-1.06 (M+1)-259.97, 22.42% at RT-2.29(M+1)-323.86).

Following LCMS analysis, the reaction mass was stirred for additional 1h, then poured into ice cold water (100 L), to give a white solid thatwas filtered and washed with water (20 L). The crude solid compound wasfurther washed with n-hexane (20 L) and dried under high vacuum toafford ethyl 5-bromo-3-methyl-6-oxo-1, 6-dihydropyridine-2-carboxylateas off white solid. Yield: 6 Kg (66.6%); MS (ESI) m/z 260.09 [M+1]+;UPLC: 66.49% (96.85% by HPLC); 1H NMR (400 MHz, DMSO-d6) δ: 11.53 (brs,1H), 7.99 (s, 1H), 4.23 (q, 2H), 2.27 (brs, 3H), 1.28 (t, 3H).

D. Preparation of ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (5)

To a stirring solution of ethyl 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxylate (1 Kg, 1 equiv, 3.84 moles) in ethanol(5 L) was added 30% aq. ammonia (7 L). The round bottom flask was thenclosed and sealed to avoid ammonia from escaping out of the reactionmass. The reaction mixture was then stirred at 40° C. for 16 h andreaction progress was monitored by using TLC and LCMS analysis. LCMSanalysis of the reaction mixture showed disappearance of SM, 64.82%product at RT-1.09 ((M+1)-231.17), and some unknown byproducts 18.2% atRT-0.83 ((M+1)-232.11), 4.74% at RT-1.76 ((M+1)-262.19).

Following LCMS, the reaction mass was concentrated under reducedpressure to remove ethanol and water so as to yield a crude solidmaterial. The crude material (wet) obtained from several syntheticbatches were combined and slurried with saturated aqueous sodiumbicarbonate solution (50 L) for 2 h, filtered and then washed with water(2×10 L). The white solid thus obtained was washed with dichloromethane(20 L), and then slurried with 20% methanol in dichloromethane (30 L)for 1 h. The slurry was filtered, washed with dichloromethane (15 L),and dried under vacuum for 6 h at 60° C. to yield 2.69 Kg of5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (5) as an offwhite solid. Yield: 2.69 Kg (50.94%); MS (ESI) m/z 231[M+1]+; UPLC:99.80%; 1H NMR (400 MHz, DMSO-d6) δ: 11.85 (brs, 1H), 7.88 (s, 2H), 7.75(s, 1H), 2.14 (s, 1H).

In a separate experiment, 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide, 2.2 Kg, obtained by combining the solidfrom several synthetic batches was slurried in dichloromethane (5.0 L)for 30 min, filtered and dried under vacuum to yield 4554.1 g5-bromo-3-methyl-6-oxo-1, 6-dihydropyridine-2-carboxamide.

Synthesis of6%((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (Cpd. 107)

A. Procedure for the Purification of5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1):

Solid sodium bicarbonate (3.3 kg) and water (40.0 L, DI) were chargedinto a 45 L carboy and stirred until the sold dissolved.5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1; 1.5 kg) wasplaced in a 50-L reactor and the solution of saturated sodiumbicarbonate was added while maintaining the temperature of this reactionmixture at 18° C. HPLC analysis of the reaction mixture after 16 hshowed that the 5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide(1) had a purity of 92.8%. The solid5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide was filteredthrough a Nutsche filter (18″ polypropylene tight weave cloth). Thereactor and filter cake were rinsed with water (3.0 L) and the solid wasconditioned at ambient temperature until liquid no longer flowed out.The solid material was transferred to drying trays and dried undervacuum at 45-50° C. The dried material weighed 1.16 kg (yield −77%), andhad a purity of 92.8%. KF analysis showed 2.6% residual water.

B. Synthesis of6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2)

5-bromo-3-methyl-6-oxo-1,6-dihydropyridine-2-carboxamide (1), (1.16 kg,1.0 equiv.); 1,4-dioxane (13.8 L); and cyclohexanone (1.96 kg) wereadded to a 50-L reactor and agitated at 75-125 RPM. Sulfuric acid (0.13L) was added to the reactor using a dosing pump. The temperature of thereaction mixture was 19.5° C. at the start of addition of sulfuric acidand increased to 21.8° C. upon the complete addition of sulfuric acid.The temperature of the reaction mixture (batch temperature) was raisedto 95° C. Following stirring for 3 h, HPLC analysis of the reactionmixture indicated completion of the reaction. The batch temperature wasthen adjusted to 20-30° C. and the solvent was distilled under vacuum(28.5″/Hg, 80° C. jacket temperature) to no less than 75% of the initialreaction volume.

Following distillation, the batch temperature was adjusted to 25° C. andheld at that temperature for 13 h. The reaction mixture (batch) wasfiltered through Nutsche filter (18″), and the mother liquor was addedback to the reactor as a rinse and then added to the filter cake. Water(12 L, DI) was then added to the reactor as a rinse and then transferredto the filter cake. The filter cake was conditioned until liquid nolonger flowed out. The solid material thus obtained was transferred todrying trays and dried under vacuum at 45-50° C. The dried materialweighed 1.28 kg (82% yield) and had a purity >99%. KF analysis showed1.4% residual water. 1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.01 (s,1H), 2.82-2.92 (m, 2H), 2.38 (s, 3H), 1.75-1.65 (m, 5H), 1.43 (d, J=24Hz, 2H), 1.25-1.15 (m, 1H).

C. Synthesis ofN-(6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(4)

To a 50-L reactor was added6′-bromo-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(2) (1.23 kg); 1,4-dioxane (15.4 L),N-(6-aminopyrimidin-4-yl)cyclopropanecarboxamide (3), (0.65 kg); andcesium carbonate (1.03 kg) and the reaction mixture was agitated as itwas sparged with argon for 20 min. at ambient temperature. To thereactor was then added palladium (II) acetate (18.0 g) and xantphos(46.0 g) and sparging with argon was continued for an additional 20 min.The sparge tube was then removed and the batch temperature was adjustedto 95° C. The reaction mixture (batch) was stirred for 18 h, at whichtime, analysis by HPLC indicated the reaction was complete. Followingcompletion of the reaction, the batch temperature was adjusted to 20° C.Water (24.6 L, DI) was added to the reactor and the batch was stirredfor 1 h, followed by filtration through a Nutsche filter (18″). Themother liquor was used to rinse the reactor and then added to the filtercake. Next, acetone (6.15 L) was added as a rinse to the reactor andthen transferred to the filter cake. The filter cake was conditioneduntil no liquid flowed from the filter. Following this, the cake wasadded back to the reactor, suspended using methanol (12.0 L) andagitated at 125 RPM. The batch temperature was adjusted to 20° C. andagitation continued for 10 min. The batch was again filtered through aNutsche filter (18″) and conditioned until liquid no longer flowed fromthe filter. The solid material thus obtained was transferred to dryingtrays and dried under vacuum at 45° C. The dried material weighted 1.42kg, (98% yield) and had a purity of 97.5%. 1H NMR (500 MHz, DMSO-d6) δ10.85 (brs, 1H), 10.07 (brs, 1H), 9.09 (s, 1H), 8.53 (s, 1H), 8.46 (s,1H), 7.85 (s, 1H), 3.95-3.05 (m, 2H), 2.45 (s, 3H), 1.95-2.05 (m, 1H),1.80-1.60 (m, 5H), 1.44 (d, J=24 Hz, 2H), 1.25-1.15 (m, 1H), 0.89-0.80(m, 4H).

D. Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione(107)

N-(6-((8′-methyl-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-6′-yl)amino)pyrimidin-4-yl)cyclopropanecarboxamide(cpd. 4), (1.42 kg); tetrahydrofuran (5.7 L); and EtOH (5.7 L) wereadded to a 50-L reactor and agitated at 100 RPM. The batch temperaturewas adjusted to 20° C. To a 45-L carboy was added water (5.7 L, DI) andKOH (1.17 kg) and the contents of the carboy were agitated until asolution formed. The KOH solution was then added to the 50-L reactorfollowed by addition of ethylenediamine (2.83 L). The batch temperatureincreased to 33° C. upon addition of ethylenediamine and was readjustedto 20° C. After stirring for 16 h HPLC analysis indicated 18.6% ofunreacted compound (4) remained. A solution of KOH (1.17 kg) and water(5.7 L), therefore, was added to the reactor and stirring continued at20° C. for an additional 16 h. Following stirring, HPLC analysisindicated 1.3% of unreacted compound (4). The pH of the batch wasadjusted to 2 by the addition of concentrated HCl (11.8 kg), over a timeperiod of 2.5 h, and a solid begins to form when the batch (reactionmixture) is at a pH of 12.7. The batch temperature was adjusted to 20°C. and the mixture was agitated for 10 minutes following which the batchcontaining solid material was filtered through a Nutsche filter (18″).

The reactor was then rinsed with water (14.15 L, DI) and the aqueousrinse was transferred to the filter while manually suspending the solidin the wash. A second rinse was performed using water (14.15 L, DI) andthe rinse was transferred again to the filter while manually suspendingthe solid in the wash. Sodium bicarbonate (1.3 kg) and water (26.0 L,DI) were then added to the rinsed 50-L reactor and the filter cake wasslowly introduced into the reactor over a time period of about 30 min toavoid excess gas liberation. The resulting suspension was agitated for 2h followed by filtration through a Nutsche filter (18″). The filter cakewas washed with water (15.0 L) and allowed to condition overnight. Thefilter cake was once again suspended in an aqueous solution of sodiumbicarbonate, agitated for 2 h and filtered through a Nutsche filter(18″). Following washing with water, the filter cake was allowed tocondition overnight and then transferred to drying trays and dried undervacuum at 45° C. The dried batch weighed 1.05 kg, (80% yield) and had apurity of 98.5%. IC analysis showed 0.7% chloride. 1H NMR (500 MHz,DMSO-d6) δ 10.20 (s, 1H), 9.68 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.97(brs, 2H), 6.42 (s, 1H), 3.00-2.90 (m, 2H), 2.43 (s, 3H), 1.80-1.60 (m,5H), 1.5 (d, J=24 Hz, 2H), 1.25-1.12 (m, 1H).

E. Synthesis of6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dionehydrochloride (107 HCl)

6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-TH-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione((107), (0.99 kg)) was added to a 50-L vessel. To a separate 45-L carboywere added tetrahydrofuran (8.22 L), ethanol (8.22 L), and water (8.22L, DI). This solution was then transferred to the 50-L vessel containingcompound 9107) and the temperature of the reaction mixture was adjustedto 5° C. To the cold reaction mixture was added KOH (0.45 kg) and theentire mixture was agitated until a solution formed. The solution wasthen transferred to the 45-L carboy and then passed, under vacuum,through a polish filter (0.3 u Hepa Cap polish filter) back to the 50-Lvessel.

The temperature of the solution (batch) was adjusted to 5° C. and the pHwas adjusted to pH 1 by the addition of concentrated HCl (37%, 1.17 L).The temperature of the acidic batch was adjusted to 20° C. followingwhich the batch was agitated for 16 h. Seed crystals (9.2 g) were addedto the batch and the agitation was continued for 16 h. After agitation,the batch was filtered through a Nutsche filter (18″) and the reactorrinsed once with the mother liquor. The rinse was added to the filtercake, followed rinsing of the filter cake with a solution of THF,ethanol and water (1:1:1). After conditioning the filter cake overnight,it was transferred to drying trays and dried under vacuum at 45° C. Thedried batch weighed 1.12 kg, 102% yield, with 4.0% water (KF oven). 1HNMR (500 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.68 (s, 1H), 8.47 (s, 1H), 8.09(s, 1H), 7.97 (brs, 2H), 6.42 (s, 1H), 3.00-2.90 (m, 2H), 2.43 (s, 3H),1.80-1.60 (m, 5H), 1.5 (d, J=24 Hz, 2H), 1.25-1.12 (m, 1H). XRPD (Cu, °20 (Theta) values): 3.5 (s), 8.5 (1), 10.5 (m), 14 (s), 17 (s), 19.5(s), 27 (m).

Biological Studies Example 249: Mnk Biochemical Enzymatic Assay

Compounds are screened for Mnk inhibition using the ADP-Glo kinase assaykit (Promega, catalogue No. V9101). All kinase reactions are performedin Reaction Buffer E (15 mM HEPES pH7.4, 20 mM NaCl, 1 mM EGTA, 10 mMMgCl₂, 0.1 mg/ml BGG, and 0.02% Tween-20). Final Mnk1 reactionscontained 10 nM recombinant Mnk1 (Life Technologies, PR9138A), 100 μMMnk substrate peptide Ac-TATKSGSTTKNR-NH₂ (American Peptide Company),300 μM ATP, and varying concentrations of the inhibitory compound ofinterest. Final Mnk2 reactions contained 3 nM recombinant Mnk2 (LifeTechnologies, PV5607), 50 μM Mnk substrate peptide Ac-TATKSGSTTKNR-NH₂(American Peptide Company), 10 μM ATP, and varying concentrations of theinhibitory compound of interest. Final DMSO concentration in eachreaction is 1%.

Kinase reactions are carried out in 96-well half-area white flat-bottompolystyrene plates in a final volume of 25 μl. Mnk1/2 enzymes arepre-incubated with compound and peptide substrate for 5 minutes prior tothe addition of ATP. After the addition of ATP, kinase reactions areincubated at room temperature for 40 minutes. Reactions are subsequentlystopped by the addition of 25 μl of ADP-Glo Reagent and incubating foran additional 40 minutes. The final luminescent signal used for kinaseactivity readout is produced by the addition of 45 μl of KinaseDetection Reagent (ADP-Glo kit, Promega) and incubating for 40 minutes.The luminescent signal is detected using a Victor 2 multilabel counter(Perkin Elmer) and the concentration of compound necessary to achieveinhibition of enzyme activity by 50% (IC₅₀) is calculated using signalsfrom an 8-point compound dilution series.

The results of these assays are set forth in Table 1 below. To this end,IC₅₀ values of less than 0.01 μM are labelled as “+++”, from 0.01 to 0.1μM are labelled as “++”, and greater than 0.1 to 10.0 μM are labelled as“+” (NA means “not available”).

TABLE 1 Mnk Biochemical Enzymatic Assay (IC₅₀) Cpd. IC₅₀ Cpd. IC₅₀ No.Mnk1 Mnk2 No. Mnk1 Mnk2 1 NA + 25 NA + 2 ++ ++ 26 ++ + 3 NA + 27 ++ ++ 4NA + 28 ++ ++ 5 NA + 29 +++ +++ 6 +++ ++ 30 +++ +++ 7 ++ +++ 31 ++ ++ 8++ ++ 32 NA + 9 ++ ++ 33 ++ ++ 10 +++ +++ 34 ++ ++ 11 ++ ++ 35 +++ +++12 ++ ++ 36 +++ +++ 13 ++ ++ 37 ++ ++ 14 ++ +++ 38 +++ +++ 15 NA + 39+++ +++ 16 +++ ++ 40 NA + 17 NA + 41 + ++ 18 +++ ++ 42 +++ +++ 19 NA +43 +++ +++ 20 ++ +++ 44 +++ +++ 21 +++ +++ 45 +++ +++ 22 +++ +++ 46 ++++++ 23 +++ +++ 47 +++ +++ 24 +++ +++ 48 +++ +++ 49 +++ +++ 75 ++ ++ 50+++ +++ 76 +++ +++ 51 +++ +++ 77 +++ +++ 52 +++ +++ 78 +++ +++ 53 ++ ++79 ++ +++ 54 ++ +++ 80 +++ +++ 55 +++ +++ 81 + + 56 +++ +++ 82 ++ ++ 57+++ +++ 83 +++ +++ 58 +++ +++ 84 +++ +++ 59 + ++ 85 +++ +++ 60 +++ +++86 +++ +++ 61 +++ +++ 87 +++ +++ 62 +++ +++ 88 +++ +++ 63 +++ +++ 89 ++++++ 64 ++ ++ 90 +++ +++ 65 +++ +++ 91 +++ +++ 66 +++ +++ 92 +++ +++ 67++ +++ 93 +++ +++ 68 + + 94 +++ +++ 69 +++ +++ 95 +++ +++ 70 +++ +++ 96+++ +++ 71 + + 97 +++ +++ 72 +++ +++ 98 +++ +++ 73 +++ +++ 99 +++ +++ 74+++ +++ 100 +++ +++ 101 +++ +++ 127 +++ +++ 102 +++ +++ 128 +++ +++ 103+++ +++ 129 +++ +++ 104 +++ +++ 130 +++ ++ 105 +++ +++ 131 ++ +++ 106+++ +++ 132 NA NA 107 +++ +++ 133 NA +++ 108 +++ +++ 134 NA NA 109 ++++++ 135 NA NA 110 +++ +++ 136 NA NA 111 +++ +++ 137 NA NA 112 +++ +++138 NA + 113 +++ +++ 139 NA NA 114 +++ +++ 140 NA NA 115 +++ +++ 141 NANA 116 +++ +++ 142 +++ +++ 117 +++ +++ 143 +++ +++ 118 NA +++ 144 NA NA119 NA +++ 145 +++ +++ 120 NA +++ 146 +++ +++ 121 NA +++ 147 NA NA 122NA +++ 148 NA NA 123 NA +++ 149 NA NA 124 NA +++ 150 NA NA 125 NA +++151 NA + 126 +++ +++ 152 NA NA 153 NA + 179 NA NA 154 NA NA 180 NA NA155 NA +++ 181 ++ ++ 156 NA ++ 182 NA NA 157 NA +++ 183 NA NA 158 NA ++184 NA NA 159 NA NA 185 NA NA 160 NA +++ 186 NA NA 161 NA + 187 +++ +++162 NA ++ 188 NA +++ 163 NA ++ 189 NA +++ 164 NA +++ 190 NA + 165 ++ ++191 NA +++ 166 NA NA 192 NA +++ 167 NA NA 193 NA +++ 168 NA NA 194 NA+++ 169 NA +++ 195 NA +++ 170 +++ +++ 196 NA +++ 171 NA NA 197 NA +++172 NA NA 198 NA + 173 NA NA 199 NA NA 174 NA NA 200 NA + 175 NA NA 201NA + 176 NA NA 202 NA ++ 177 NA NA 203 NA + 178 NA NA 204 NA ++ 205 NANA 227 NA NA 206 NA +++ 228 NA NA 207 NA +++ 229 NA NA 208 NA +++ 230 NA+++ 209 NA NA 231 NA +++ 210 NA NA 232 NA +++ 211 NA + 233 NA +++ 212 NANA 234 NA +++ 213 NA ++ 235 NA +++ 214 NA ++ 236 NA +++ 215 NA ++ 237 NANA 216 NA ++ 238 NA NA 217 NA + 239 NA NA 218 NA + 240 NA NA 219 NA +++241 NA NA 220 NA +++ 242 NA NA 221 NA Inactive 243 NA NA 222 NA +++ 244NA NA 223 NA +++ 245 NA NA 224 NA Inactive 246 NA NA 225 NA +++ 247 NANA 226 NA +++

Example 250: peIF4E Signaling Cellular Assay

Phosphorylated eIF4E is assayed using the CisBio peIF4E HTRF® assay kit(CisBio, catalogue No. 64EF4PEG). Cells are plated in 96-welltissue-culture treated plate in appropriate growth medium (90 μL).Compounds (10×) are diluted using 3-fold serial dilutions in cellculture medium and added to cells. Plates are incubated for 2 hrs at 37°C. The cell supernatant is carefully removed either by aspiratingsupernatant or by flicking the plate. Immediately 50 μL of supplementedlysis buffer (1×) is added and incubated for at least 30 minutes at roomtemperature under shaking. After homogenization by pipeting up and down,16 μL of cell lysate is transferred from the 96-well cell-culture plateto a 384-well small volume white plate. 4 μL of premixed antibodysolutions (vol/vol) is prepared in the detection buffer and added. Theplate is covered with a plate sealer and incubated overnight at roomtemperature. The fluorescence emissions at two different wavelengths areread (665 nm and 620 nm) on a Wallac Victor2. Emission ratios areconverted into percent inhibitions and imported into GraphPad Prismsoftware. The concentration of compound necessary to achieve inhibitionof enzyme activity by 50% (IC₅₀) is calculated using concentrationsranging from 20 μM to 0.1 nM (12-point curve). IC₅₀ values aredetermined using a nonlinear regression model available in GraphPadPrism 5.

The results of these assays are set forth in Table 2 below. To this end,IC₅₀ values of less than 0.05 μM are labelled as “+++”, from 0.05 to 1.0μM are labelled as “++”, greater than 1.0 to 100 μM are labelled as “+”,and NA means “not available”.

TABLE 2 peIF4E Signaling Cellular Assay (IC₅₀) Cpd. Cpd. Cpd. No. IC₅₀No. IC₅₀ No. IC₅₀ 1 NA 26 NA 51 +++ 2 + 27 ++ 52 +++ 3 NA 28 NA 53 ++ 4NA 29 +++ 54 ++ 5 NA 30 +++ 55 +++ 6 ++ 31 ++ 56 +++ 7 ++ 32 NA 57 ++8 + 33 ++ 58 +++ 9 ++ 34 + 59 + 10 +++ 35 +++ 60 +++ 11 + 36 +++ 61 +++12 ++ 37 ++ 62 +++ 13 + 38 +++ 63 +++ 14 ++ 39 +++ 64 ++ 15 NA 40 NA 65+++ 16 ++ 41 + 66 +++ 17 NA 42 +++ 67 ++ 18 ++ 43 +++ 68 NA 19 NA 44 +++69 ++ 20 ++ 45 +++ 70 +++ 21 +++ 46 +++ 71 ++ 22 +++ 47 ++ 72 + 23 +++48 +++ 73 +++ 24 +++ 49 +++ 74 ++ 25 NA 50 +++ 75 + 76 +++ 102 ++ 128+++ 77 +++ 103 +++ 129 ++ 78 +++ 104 ++ 130 + 79 + 105 +++ 131 + 80 +++106 ++ 132 NA 81 + 107 +++ 133 ++ 82 + 108 +++ 134 NA 83 +++ 109 +++ 135NA 84 +++ 110 +++ 136 NA 85 +++ 111 +++ 137 NA 86 +++ 112 ++ 138 + 87+++ 113 + 139 NA 88 +++ 114 +++ 140 NA 89 +++ 115 +++ 141 NA 90 ++ 116++ 142 ++ 91 +++ 117 +++ 143 +++ 92 ++ 118 + 144 NA 93 +++ 119 +++ 145+++ 94 +++ 120 +++ 146 + 95 +++ 121 +++ 147 NA 96 +++ 122 +++ 148 NA 97+++ 123 +++ 149 NA 98 +++ 124 ++ 150 NA 99 +++ 125 + 151 + 100 +++ 126 +152 NA 101 ++ 127 +++ 153 NA 154 NA 180 NA 206 NA 155 + 181 + 207 NA 156++ 182 NA 208 ++ 157 ++ 183 NA 209 NA 158 ++ 184 NA 210 NA 159 NA 185 NA211 NA 160 ++ 186 NA 212 NA 161 + 187 +++ 213 + 162 + 188 +++ 214 +163 + 189 ++ 215 + 164 ++ 190 NA 216 + 165 + 191 ++ 217 + 166 NA 192 ++218 NA 167 NA 193 +++ 219 ++ 168 NA 194 +++ 220 ++ 169 +++ 195 +++ 221NA 170 ++ 196 +++ 222 +++ 171 NA 197 +++ 223 +++ 172 NA 198 NA 224 NA173 NA 199 NA 225 + 174 NA 200 + 226 + 175 NA 201 NA 227 + 176 NA 202 NA228 ++ 177 NA 203 NA 229 + 178 NA 204 NA 230 + 179 NA 205 NA 231 +++ 232++ 238 ++ 244 ++ 233 ++ 239 +++ 245 NA 234 +++ 240 ++ 246 NA 235 + 241+++ 247 NA 236 ++ 242 ++ 237 +++ 243 ++

Example 251: Pharmacokinetic Studies

Groups of Balb/c mice or Sprague-Dawley rats (n≥3 per dose group) areadministered single doses of test compound. Compounds are formulatedeither as solutions in 10% N-methylpyrrolidone, 90% polyethyleneglycol400 or as suspensions in 0.5% methylcellulose in water for oral gavageadministration at a nominal dose level of 10 mg/kg. Compounds areformulated in 10% dimethylisosorbide, 15% ethanol, 35% propylene glycol,and 40% saline (or 40% D5W) for intravenous administration at a nominaldose level of 1 mg/kg. For intravenously dosed animals, blood samplesare collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 h post dose. Fororally dosed animals, blood samples are collected at 0.25, 0.5, 1, 2, 4,8, and 24 h post dose. Blood samples are collected from mice eitherserially via submandibular vein (approximately 0.1 mL each) orterminally via cardiac puncture (approximately 0.5 mL each). Bloodsamples are collected serially from rats via jugular vein catheter(approximately 0.2 mL each). Each blood sample is collected into a tubethat is chilled and contains potassium EDTA as the anticoagulant. Plasmais separated and stored at approximately −80 C until analysis. Followingprotein precipitation with acetonitrile containing an internal standard,plasma samples are analyzed using a liquidchromatography/high-resolution mass spectrometry (LC-HRMS) method todetermine plasma concentrations. Plasma concentration versus time dataare subjected to noncompartmental pharmacokinetic analysis usingPhoenix™ Winnonlin® (Certara LP) to determine pharmacokineticparameters, including Area Under the Curve (AUC), Clearance (Cl), Volumeof Distribution at Steady-State (Vss), and terminal half-life (T1/2).Data from orally and intravenously dose are highlighted in Tables 3 and4, respectively.

TABLE 3 Pharmacokinetics Parameters in Balb/c Mice Following a SingleOral Gavage Administration at 10 mg/kg Cpd. T1/2 Tmax Cmax Tlast AUClastNo. Formulation (h) (h) (ug/mL) (h) (h*ug/mL) Gender 9 0.5 MC 0.831 0.505.05 8 4.83 M 10 10 NMP/90 PEG400 1.87 0.50 1.72 8 6.42 F 10 0.5 MC 4.221.00 2.16 24 8.75 M 14 0.5 MC ND 0.50 0.405 8 0.255 M 20 0.5 MC 0.6430.50 2.24 4 2.09 F 21 0.5 MC 2.66 0.50 0.0502 4 0.109 F 22 0.5 MC 1.932.00 0.371 8 1.62 F 23 0.5 MC 3.49 1.00 0.0175 8 0.0757 F 24 0.5 MC 1.912.00 0.192 8 0.921 F 35 10 NMP/90 PEG400 3.46 2.00 6.93 24 71.29 F 430.5 MC 6.75 2.00 0.0218 8 0.132 F 45 0.5 MC 7.55 2.00 0.00916 8 0.0429 F50 0.5 MC 8.43 4.00 0.0472 24 0.464 F 50 5 NMP/95 PEG400 2.82 8.00 0.5524 7.15 F 51 0.5 MC 7.38 2.00 3.16 24 31.3 F 51 5 NMP/95 PEG400 8.368.00 2.44 24 35.8 F 52 0.5 MC 5.41 4.00 3.37 24 38.1 F 52 10 NMP/90PEG400 3.56 0.25 1.7 24 22.3 F 54 0.5 MC 0.743 0.50 1.05 4 1.23 F 54 10NMP/90 PEG400 3.22 0.25 1.9 24 3.64 F 55 5 NMP/95 PEG400 2.61 1.00 6.1724 56.9 F 56 10 NMP/90 PEG400 ND BQL BQL ND ND F 58 0.5 MC 5.32 2.000.69 24 5.43 F 60 10 NMP/90 PEG400 2.21 1.00 0.036 4 0.0782 F 70 10NMP/90 PEG400 2.00 0.25 0.983 8 1.47 F 70 10 NMP/90 PEG400 3.74 0.501.65 8 2.01 F 88 0.5 MC 2.97 0.50 0.81 8 2.04 F 94 10 NMP/90 PEG400 20.50 1.8 8 6.07 F 98 10 NMP/90 PEG400 3.1 0.30 1.2 8 4.18 F 99 10 NMP/90PEG400 1.6 0.30 0.4 8 1.38 F 102 10 NMP/90 PEG400 1.4 0.30 1.8 F 103 10NMP/90 PEG400 2.1 0.30 2.5 8 4.65 F 107 10 NMP/90 PEG400 5.3 1 0.95 82.76 F 108 10 NMP/90 PEG400 0.3 0.30 0.044 F 109 10 NMP/90 PEG400 2.50.30 0.63 F 110 10 NMP/90 PEG400 2.6 0.30 1.7 F Abbreviations:NMP—N-methylpyrrolidone; PEG400—polyethyleneglycol 400;MC—methylcellulose

TABLE 4 Pharmacokinetic Pparameters in Balb/c Following a SingleIntravenous Bolus Administration at 1 mg/kg Cpd. Cl_obs T1/2 VssAUCINF_obs No. Formulation (mL/min/kg) (h) (L/kg) (h*ug/mL) Gender 10 10DMI/15 EtOH/35 PG/40 Saline 42.1 2.80 5.45 0.396 F 50 10 DMI/15 EtOH/35PG/40 Saline 18.8 2.47 3.18 0.887 F 51 10 DMI/15 EtOH/35 PG/40 Saline6.66 5.78 2.79 2.50 F 70 10 DMI/15 EtOH/35 PG/40 D5W 50.1 0.561 1.800.333 F 88 10 DMA/15 EtOH/35 PEG300/40 D5W 61 1.3 3.03 0.273 F 94 10DMA/15 EtOH/35 PEG300/40 D5W 20.5 5.81 12.2 0.812 F 98 10 DMA/15 EtOH/35PEG300/40 D5W 46.6 1.79 3.56 0.358 F 103 10 DMA/15 EtOH/35 PEG300/40 D5W27.8 1.51 2.49 0.6 F 107 10 DMA/15 EtOH/35 PEG300/40 D5W 33.2 2.91 3.210.502 F Abbreviations: DMI—dimethylisosorbide; EtOH—ethanol;PG—propylenglycol; D5W—5% dextrose in water

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet areincorporated herein by reference, in their entirety. Aspects of theembodiments can be modified, if necessary to employ concepts of thevarious patents, applications and publications to provide yet furtherembodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

1. A method for treating a disease or condition in a mammal in needthereof, the method comprising administering to the mammal atherapeutically effective amount of at least one MAP kinase interactingkinase (Mnk) inhibitor and at least one other therapeutic agent, whereinthe at least one other therapeutic agent is other than the at least oneMnk inhibitor.
 2. The method of claim 1, wherein the mammal is a human.3. The method of claim 1, wherein the at least one other therapeuticagent is an anti-cancer agent.
 4. The method of claim 3, wherein theanti-cancer agent is a chemo-therapeutic drug.
 5. The method of claim 3,wherein the anti-cancer agent is selected from folate antagonists,antiproliferative agents, antimitotic agents, microtubule inhibitingagents, DNA damaging agents, DNA synthesis inhibitors, DNA interactiveagents, DNA repair inhibitors, antiplatelet agents, antimetabolites,hormones, hormone analogs, aromatase inhibitors, fibrinolytic agents,antimigratory agents, antisecretory agents, immunosuppressives,anti-angiogenic compounds, growth factor inhibitors, angiotensinreceptor blocker, nitric oxide donors, anti-sense oligonucleotides,antibodies, chimeric antigen receptors, cell cycle inhibitors,differentiation inducers, mTOR inhibitors, topoisomerase inhibitors,corticosteroids, growth factor signal transduction kinase inhibitors,mitochondrial dysfunction inducers, caspase activators, and inhibitorsof chromatin function.
 6. The method of claim 1, wherein the Mnkinhibitor is a compound according to Formula (I):

or a stereoisomer, tautomer, solvate, or pharmaceutically acceptablesalt thereof, wherein: W¹ and W² are independently O, S or N—OR′,wherein R′ is lower alkyl; Y is —N(R⁵)—, —O—, —S—, —C(O)—, —S═O,—S(O)₂—, or —CHR⁹—, wherein R⁵ is hydrogen, cyano, or lower alkyl; R¹ ishydrogen, lower alkyl, cycloalkyl or heterocyclyl, wherein any loweralkyl, cycloalkyl or heterocyclyl is optionally substituted with 1, 2 or3 J groups; n is 1, 2 or 3; R² and R³ are each independently hydrogen,alkyl, alkenyl, alkynyl, aryl, araalkylene, heteroaryl,heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, orheterocyclylalkylene, wherein any alkyl, aryl, araalkylene, heteroaryl,heteroarylalkylene, cycloalkyl, cycloalkylalkylene, heterocyclyl, orheterocyclylalkylene is optionally substituted with 1, 2 or 3 J groups;or R² and R³ taken together with the carbon atom to which they areattached form a cycloalkyl or heterocyclyl, wherein any cycloalkyl orheterocyclyl is optionally substituted with 1, 2 or 3 J groups; R^(4a)and R^(4b) are each independently hydrogen, halogen, hydroxyl, thiol,hydroxyalkylene, cyano, alkyl, alkoxy, acyl, thioalkyl, alkenyl,alkynyl, cycloalkyl, aryl, or heterocyclyl; R⁶, R⁷ and R⁸ are eachindependently hydrogen, hydroxy, halogen, cyano, amino, alkyl, alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene,alkylaminyl, alkylcarbonylaminyl, cycloalkylcarbonylaminyl,cycloalkylaminyl, heterocyclylaminyl, heteroaryl, or heterocyclyl, andwherein any amino, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl,cycloalkylalkylene, cycloalkylalkenylene, amino, alkylaminyl,alkylcarbonylaminyl, cycloalkylcarbonylaminyl, cycloalkylaminyl,heterocyclylaminyl, heteroaryl, or heterocyclyl is optionallysubstituted with 1, 2 or 3 J groups; or R⁵ and R⁸ taken together withthe atoms to which they are attached form a fused heterocyclyloptionally substituted with 1, 2 or 3 J groups; or R⁷ and R⁸ takentogether with the atoms to which they are attached form a fusedheterocyclyl or heteroaryl optionally substituted with 1, 2 or 3 Jgroups; wherein each J group is independently —SH, —SR⁹, —S(O)R⁹,—S(O)₂R⁹, —S(O)NH₂, —S(O)NR⁹R⁹, —NH₂, —NR⁹R⁹, —COOH, —C(O)OR⁹, —C(O)R⁹,—C(O)—NH₂, —C(O)—NR⁹R⁹, hydroxy, cyano, halogen, acetyl, alkyl, loweralkyl, alkenyl, alkynyl, alkoxy, haloalkyl, thioalkyl, cyanoalkylene,alkylaminyl, NH₂—C(O)-alkylene, NR⁹R⁹—C(O)-alkylene, —CHR⁹—C(O)-loweralkyl, —C(O)-lower alkyl, alkylcarbonylaminyl, cycloalkyl, cycloalkylalkylene, cycloalkylalkenylene, cycloalkylcarbonylaminyl,cycloalkylaminyl, —CHR⁹—C(O)-cycloalkyl, —C(O)— cycloalkyl,—CHR⁹—C(O)-aryl, —CHR⁹-aryl, —C(O)-aryl, —CHR⁹—C(O)-heterocycloalkyl,—C(O)-heterocycloalkyl, heterocyclylaminyl, or heterocyclyl; or any twoJ groups bound to the same carbon or hetero atom may be taken togetherto form oxo; and R⁹ is hydrogen, lower alkyl or —OH.
 7. The method ofclaim 6, wherein n is
 1. 8. The method of claim 6, wherein R² and R³taken together with the carbon atom to which they are attached form acycloalkyl or heterocyclyl, wherein any cycloalkyl or heterocyclyl isoptionally substituted with 1, 2 or 3 J groups selected from the groupconsisting of halogen, —CN, methyl, difluoroethylene, trifluoroethylene,and methylenenitrile.
 9. The method of claim 8, wherein R² and R³ takentogether with the carbon atom to which they are attached form acyclohexyl or piperidine ring.
 10. The method of claim 6, wherein:R^(4a) and R^(4b) are each independently hydrogen, halogen, or alkyl; R⁶and R⁸ are hydrogen; and R⁷ is amino, cycloalkyl carbonylaminyl,heterocyclylaminyl, or cycloalkyl alkylene.
 11. The method of claim 6,wherein and W is O or S, and Y is —N(R⁵)—, wherein R⁵ is hydrogen. 12.The method of claim 6, wherein the compound according to Formula (I) isselected from the group consisting of:

or a stereoisomer, tautomer, solvate, or pharmaceutically acceptablesalt thereof.
 13. The method of claim 1, wherein the disease orcondition is associated with overexpression or hyperactivation ofeukaryotic initiation factor 4E (eIF4E).
 14. The method of claim 1,wherein the disease or condition is cancer.
 15. The method of claim 14,wherein the cancer is selected from a solid tumor and a hematologicalcancer.
 16. The method of claim 14, wherein the cancer is selected fromcolorectal cancer, bladder cancer, gastric cancer, esophageal cancer,head and neck cancer, CNS cancer, malignant glioma, glioblastoma,hepatocellular cancers, thyroid cancer, lung cancer, non-small cellcancer, small cell lung cancer, melanoma, myeloma, pancreatic cancer,pancreatic carcinoma, renal cell carcinoma, cervical cancer, urothelialcancer, prostate cancer, castration-resistant prostate cancer, ovariancancer, breast cancer, triple-negative breast cancer, leukemia, Hodgkinslymphoma, non-Hodgkins lymphoma, B-cell lymphoma, T-cell lymphoma, hairycell lymphoma, diffuse large B-cell lymphoma, Burkitts lymphoma,multiple myeloma, and myelodysplastic syndrome.
 17. The method of claim14, wherein the mammal exhibits resistance to cancer therapy with anmTOR inhibitor.
 18. The method of claim 1, wherein the disease orcondition is selected from an inflammatory disease.
 19. The method ofclaim 18, wherein the disease or condition is an inflammatory diseaseselected from inflammatory arthritis, rheumatoid arthritis, psoriaticarthritis, osteoarthritis, juvenile rheumatoid arthritis, Reiter'ssyndrome, rheumatoid traumatic arthritis, rubella arthritis, acutesynovitis and gouty arthritis; sunburn, psoriasis, erythrodermicpsoriasis, pustular psoriasis, eczema, dermatitis, acute or chronicgraft formation, atopic dermatitis, contact dermatitis, urticaria andscleroderma; inflammatory bowel disease, Crohn's disease, ulcerativecolitis, colitis, and diverticulitis; nephritis, urethritis,salpingitis, oophoritis, endomyometritis, spondylitis, systemic lupuserythematosus, multiple sclerosis, asthma, meningitis, myelitis,encephalomyelitis, encephalitis, phlebitis, thrombophlebitis, asthma,bronchitis, chronic obstructive pulmonary disease (COPD), inflammatorylung disease, adult respiratory distress syndrome, allergic rhinitis;endocarditis, osteomyelitis, rheumatic fever, rheumatic pericarditis,rheumatic endocarditis, rheumatic myocarditis, rheumatic mitral valvedisease, rheumatic aortic valve disease, prostatitis, prostatocystitis,spondoarthropathies ankylosing spondylitis, synovitis, tenosynovotis,myositis, pharyngitis, polymyalgia rheumatica, shoulder tendonitis orbursitis, gout, pseudo gout, vasculitides, granulomatous thyroiditis,lymphocytic thyroiditis, invasive fibrous thyroiditis, acutethyroiditis; Hashimoto's thyroiditis, Kawasaki's disease, Raynaud'sphenomenon, Sjogren's syndrome, neuroinflammatory disease, sepsis,conjunctivitis, keratitis, iridocyclitis, optic neuritis, otitis,lymphoadenitis, nasopaharingitis, sinusitis, pharyngitis, tonsillitis,laryngitis, epiglottitis, bronchitis, pneumonitis, stomatitis,gingivitis, oesophagitis, gastritis, peritonitis, hepatitis,cholelithiasis, cholecystitis, glomerulonephritis, goodpasture'sdisease, crescentic glomerulonephritis, pancreatitis, endomyometritis,myometritis, metritis, cervicitis, endocervicitis, exocervicitis,parametritis, tuberculosis, vaginitis, vulvitis, silicosis, sarcoidosis,pneumoconiosis, pyresis, inflammatory polyarthropathies, psoriatricarthropathies, intestinal fibrosis, bronchiectasis and enteropathicarthropathies.